U.S. patent application number 14/808609 was filed with the patent office on 2015-11-19 for preventive or therapeutic agent for pain associated with herpes zoster in acute phase.
The applicant listed for this patent is KYUSHU UNIVERSITY, NIPPON CHEMIPHAR CO., LTD.. Invention is credited to Kazuhide INOUE, Yuta MATSUMURA, Makoto TSUDA.
Application Number | 20150328231 14/808609 |
Document ID | / |
Family ID | 46024510 |
Filed Date | 2015-11-19 |
United States Patent
Application |
20150328231 |
Kind Code |
A1 |
INOUE; Kazuhide ; et
al. |
November 19, 2015 |
PREVENTIVE OR THERAPEUTIC AGENT FOR PAIN ASSOCIATED WITH HERPES
ZOSTER IN ACUTE PHASE
Abstract
A P2X.sub.4 receptor antagonist such as paroxetine, a
diazepinedione derivative having the following formula (IX) is used
as an agent for preventing or treating zoster-associated pain in
acute phase: ##STR00001## wherein R.sup.1 is hydrogen, a C.sub.1-8
alkyl group, or the like; each of R.sup.2 and R.sup.3 is hydrogen,
a C.sub.1-8 alkyl group, or the like; each of R.sup.4 and R.sup.5
is hydrogen or the like; and W is a five-membered or six-membered
heterocyclic ring optionally having one or more substituents and
comprising one to four nitrogen atoms as the members of the
ring.
Inventors: |
INOUE; Kazuhide;
(Fukuoka-shi, JP) ; TSUDA; Makoto; (Fukuoka-shi,
JP) ; MATSUMURA; Yuta; (Fukuoka-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KYUSHU UNIVERSITY
NIPPON CHEMIPHAR CO., LTD. |
Fukuoka-shi
Tokyo |
|
JP
JP |
|
|
Family ID: |
46024510 |
Appl. No.: |
14/808609 |
Filed: |
July 24, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13882205 |
Aug 9, 2013 |
9115123 |
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PCT/JP2011/075244 |
Nov 2, 2011 |
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14808609 |
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Current U.S.
Class: |
514/220 |
Current CPC
Class: |
C07D 413/10 20130101;
A61K 31/4525 20130101; A61P 29/00 20180101; A61K 31/335 20130101;
C07D 313/12 20130101; A61K 31/135 20130101; A61K 31/551 20130101;
A61K 31/15 20130101; C07D 223/28 20130101; A61P 25/02 20180101;
C07D 413/12 20130101; A61K 31/55 20130101; A61K 31/343 20130101;
C07D 405/12 20130101; A61K 31/451 20130101; A61K 31/138 20130101;
C07D 307/87 20130101; A61K 31/495 20130101; A61K 31/5513 20130101;
A61P 43/00 20180101 |
International
Class: |
A61K 31/5513 20060101
A61K031/5513 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 5, 2010 |
JP |
2010-248173 |
Claims
1. (canceled)
2. A method of treating prodrome or pain of herpes zoster in acute
phase comprising administrating an effective amount of a compound
having the following formula (VIII) or a pharmacologically
acceptable salt thereof to a patient in need thereof: ##STR00085##
wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl; R.sup.2 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, a C.sub.2-8 acylamino group, a
C.sub.2-8 acylamino group having one to three halogen atoms, a
C.sub.1-8 alkylsulfonylamino group, carboxyl, a C.sub.2-8 acyl
group, an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety, carbamoyl, a C.sub.1-8 alkylthio group, a C.sub.1-8
alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or sulfamoyl;
R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, carboxyl, a C.sub.2-8 acyl
group, or an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety; and each of R.sup.4 and R.sup.5 independently is hydrogen,
a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms.
3. The method according to claim 2, wherein R.sup.1 is
hydrogen.
4. The method according to claim 2, wherein each of R.sup.4 and
R.sup.5 is hydrogen.
5. The method according to claim 2, wherein R.sup.2 is a C.sub.2-8
acylamino group having one to three halogen atoms.
6. The method according to claim 2, wherein R.sup.3 is
hydrogen.
7. A method of preventing postherpetic neuralgia comprising
administrating an effective amount of P2X.sub.4 receptor antagonist
to a patient of the acute phase pain of herpes zoster, wherein the
P2X.sub.4 receptor antagonist is a compound having the following
formula (VIII) or a pharmacologically acceptable salt thereof:
##STR00086## wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group,
a C.sub.2-8 alkenyl group, a C.sub.1-8 alkyl group having one to
three halogen atoms, or a C.sub.1-3 alkyl group having phenyl;
R.sup.2 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, a C.sub.2-8 acylamino group, a
C.sub.2-8 acylamino group having one to three halogen atoms, a
C.sub.1-8 alkylsulfonylamino group, carboxyl, a C.sub.2-8 acyl
group, an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety, carbamoyl, a C.sub.1-8 alkylthio group, a C.sub.1-8
alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or sulfamoyl;
R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, carboxyl, a C.sub.2-8 acyl
group, or an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety; and each of R.sup.4 and R.sup.5 independently is hydrogen,
a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms.
8. The method according to claim 7, wherein R.sup.1 is
hydrogen.
9. The method according to claim 7, wherein each of R.sup.4 and
R.sup.5 is hydrogen.
10. The method according to claim 7, wherein R.sup.2 is a C.sub.2-8
acylamino group having one to three halogen atoms.
11. The method according to claim 7, wherein R.sup.3 is
hydrogen.
12. A method of preventing postherpetic neuralgia comprising
administrating an effective amount of a combination of an
anti-herpetic drug with P2X.sub.4 receptor antagonist to a patient
of the acute phase pain of herpes zoster, wherein the P2X.sub.4
receptor antagonist is a compound having the following formula
(VIII) or a pharmacologically acceptable salt thereof: ##STR00087##
wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl; R.sup.2 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, a C.sub.2-8 acylamino group, a
C.sub.2-8 acylamino group having one to three halogen atoms, a
C.sub.1-8 alkylsulfonylamino group, carboxyl, a C.sub.2-8 acyl
group, an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety, carbamoyl, a C.sub.1-8 alkylthio group, a C.sub.1-8
alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or sulfamoyl;
R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, carboxyl, a C.sub.2-8 acyl
group, or an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety; and each of R.sup.4 and R.sup.5 independently is hydrogen,
a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms.
13. The method according to claim 12, wherein R.sup.1 is
hydrogen.
14. The method according to claim 12, wherein each of R.sup.4 and
R.sup.5 is hydrogen.
15. The method according to claim 12, wherein R.sup.2 is a
C.sub.2-8 acylamino group having one to three halogen atoms.
16. The method according to claim 12, wherein R.sup.3 is hydrogen.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an agent for preventing or
treating zoster-associated pain in acute phase.
BACKGROUND OF THE INVENTION
[0002] Herpes zoster is a viral disease caused by a varicella
zoster virus (VZV). Initial infection of VZV is usually in
childhood to cause varicella. The infected host may acquire humoral
and cellular immunities against VZV to cease proliferation of
virus. At the same time, virus may partly be incorporated into the
peripheral end of sensory nerve fibers distributed in the skin,
ascend the sensory nerve fiber along a retrograde axonal flow, and
cause latent infection in ganglion. When the specific cellular
immunity against VZV is lowed in the host, virus is reactivated to
develop the syndrome of the herpes zoster. The reactivated virus
descends the sensory nerve fiber along an antegrade axonal flow to
reach the skin and cause zonary exanthema. The exanthema is
naturally healed generally within about three weeks.
[0003] The zoster-associated pain is generally classified into an
acute phase pain and a chronic phase pain. The chronic phase pain
is a general problem, which continues over a long term after
healing the exanthema. The chronic phase pain is called
postherpetic neuralgia, which is considered as neuropathic pain
caused by neural degeneration in central and peripheral nervous
systems (Non-patent documents 1, 2, and 3). Tricyclic
antidepressant, opioid, antiepileptic drugs or the like are used
for the present to treat postherpetic neuralgia, and their
treatment effects are reported.
[0004] On the other hand, the acute phase pain is prodrome or pain
in an acute phase, which causes neuralgia-like pain several days
before development of exanthema. It includes neuritis pain caused
by proliferated virus and inflammatory pain within the area of
exanthema. The area of exanthema can be the center of algesthesia,
and pain runs along the nerve. The strength of the pain widely
ranges from lightly stimulated symptom to heavy pain losing sleep
at night. A HSV-1 infected rat has been used as a herpes zoster
model. It has been confirmed that the rat can be spontaneously
excited without inflammatory syndrome in the spinal posterior root
ganglion. It is suggested that acute phase pain may be expressed
with spontaneous hypersthenia of the primary neuron cell body
(Non-patent document 4).
[0005] The acute phase of herpes zoster is treated for the present
by using a combination of antiviral agent such as Valaciclovir,
Aciclovir, Famciclovir or the like with an analgesic such as
NSAIDs. The NSAIDs has an effect on inflammatory pain, but no
effect on neuritis-like pain. Further, whole body administration of
opioid is sometimes used. It has been known that the
above-mentioned pharmacotherapy can have an accelerating effect of
healing exanthema, and show a partial effect on acute phase pain,
but it cannot suppress the pain completely. Therefore, nerve block
treatments, such as epidural block, stellate block, peripheral
nerve block has been used in the case that the exanthema and pain
are serious (Non-patent document 5). For the reasons mentioned
above, it has been desired to develop a method of treating acute
phase of herpes zoster pain in view of QOL of the herpes zoster
patients.
[0006] The present inventors have found that paroxetine, a
diazepinedione derivative or the like having a P2X.sub.4 receptor
antagonism can be used as an agent for preventing or treating
neuropathic pain, and filed patent applications (Patent documents 1
and 2).
[0007] The patent documents, however, do not clearly describe that
the above-mentioned compounds are available as an agent for
preventing or treating zoster-associated pain in acute phase.
PRIOR ART DOCUMENTS
Patent Documents
[0008] Patent document 1: WO 2008/020651 [0009] Patent document 2:
WO 2010/093061
Non-Patent Documents
[0009] [0010] Non-patent document 1: Oaklander A L., Pain, 2001,
92:139-145 [0011] Non-patent document 2: Watson C P, et al., Pain,
1991, 44:105-117 [0012] Non-patent document 3: Rowbotham M C, et
al., Neurobiol Dis, 1996, 3:205-214 [0013] Non-patent document 4:
Fleetwood-Walker S M, et al., J Gen Virol., 1999, 80:2433-2436
[0014] Non-patent document 5: Kazushige Kawamura et al., the
Progress of Medicine, 2007, Vol. 223, No 9:40-42
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0015] It is the object of the invention to provide an agent for
preventing or treating zoster-associated pain in acute phase.
Means for Solving the Problems
[0016] The present inventors have found that P2X.sub.4 receptor
antagonist such as paroxetine, a diazepinedione derivative or the
like can be used as an agent for preventing or treating
zoster-associated pain in acute phase, and completed the present
invention.
[0017] The present invention relates to an agent for preventing or
treating zoster-associated pain in acute phase containing P2X.sub.4
receptor antagonist as an active ingredient.
[0018] The invention also relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (I) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00002##
wherein R.sup.1 is a halogen atom; and
[0019] R.sup.2 is hydrogen, a halogen atom, nitro, cyano,
--C(O)OR.sup.3, --C(O)--NR.sup.4R.sup.5, --SO.sub.2--OR.sup.3,
--SO.sub.2--NR.sup.4R.sup.5, wherein each of R.sup.3, R.sup.4, and
R.sup.5 is hydrogen or a C.sub.1-6 alkyl group; or in the
alternative
[0020] R.sup.1 is hydrogen; and
[0021] R.sup.2 is a halogen atom, nitro, cyano, --C(O)--OR.sup.3,
--C(O)--NR.sup.4R.sup.5, --SO.sub.2--OR.sup.3,
--SO.sub.2--NR.sup.4R.sup.5, wherein each of R.sup.3, R.sup.4, and
R.sup.5 is hydrogen or a C.sub.1-6 alkyl group.
[0022] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (Ia) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00003##
wherein R.sup.1 is chloro or bromo; and
[0023] R.sup.2 is hydrogen, chloro, bromo, nitro, or cyano; or in
the alternative
[0024] R.sup.1 is hydrogen; and
[0025] R.sup.2 is chloro, bromo, nitro, or cyano.
[0026] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (II) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00004##
wherein R is a C.sub.1-4 alkyl group, a C.sub.2-4 alkynyl group,
phenyl optionally having one or more substituents selected from the
group consisting of a lower alkyl group, an alkylthio group, an
alkoxy group, a halogen atom, nitro, an acylamino group,
methylsulfonyl, and methylenedioxy, or tetrahydronaphthyl;
[0027] R.sup.1 is hydrogen; and
[0028] X is hydrogen, a C.sub.1-4 alkyl group, a trifluoroalkyl
group, hydroxyl, a halogen atom, methylthio, or an arylalkoxy
group.
[0029] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
selective serotonin reuptake inhibitor as an active ingredient.
[0030] The invention further relates to An agent for preventing or
treating zoster-associated pain in acute phase containing an agent
selected from the group consisting of imipramine, nortriptyline,
amitriptyline, desipramine, doxepin, fluoxetine, fluvoxamine,
citalopram, and a pharmacologically acceptable salt thereof as an
active ingredient.
[0031] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (III) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00005##
wherein X is S or CH.sub.2;
[0032] Y is O, S, or NH;
[0033] R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one or more halogen atoms, an aralkyl group
comprising a C.sub.1-6 alkyl moiety and a C.sub.6-10 aryl moiety, a
C.sub.2-8 alkenyl group, carboxymethyl, or an alkoxycarbonylmethyl
group comprising a C.sub.1-8 alkoxy moiety;
[0034] each of R.sup.2 and R.sup.3 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl
group having one or more halogen atoms, a C.sub.1-8 alkoxy group
having one or more halogen atoms, a halogen atom, amino, carboxyl,
hydroxyl, nitro, cyano, a C.sub.2-8 acyl group, a C.sub.6-10 aryl
group, or a five-membered or six-membered heterocyclic group;
[0035] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms; and
[0036] the double line consisting of a broken line and a solid line
is a single bond or a double bond.
[0037] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (IV) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00006##
wherein X.sup.a is O, S, or NH;
[0038] R.sup.1a is hydroxyl, tetrazolyl, N(R.sup.5a)(R.sup.6a), a
C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a C.sub.1-8
alkyl group having one or more halogen atoms, a C.sub.1-8 alkoxy
group having one or more halogen atoms, or a C.sub.6-10 aryl group,
wherein R.sup.5a is hydrogen or a C.sub.1-8 alkyl group, and
R.sup.6a is hydrogen, a C.sub.1-8 alkyl group, or a C.sub.2-8 acyl
group; each of R.sup.2a and R.sup.3a independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms; and
[0039] R.sup.4a is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one or more halogen
atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl,
tetrazolyl, cyano, a C.sub.6-10 aryl group, or a five-membered or
six-membered heterocyclic group.
[0040] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (IVa) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00007##
wherein X.sup.b is O, S, or NH;
[0041] R.sup.1b is a halogen atom, hydroxyl, tetrazolyl,
N(R.sup.5b)(R.sup.6b), a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl group having one or more halogen
atoms, a C.sub.1-8 alkoxy group having one or more halogen atoms,
or a C.sub.6-10 aryl group, wherein R.sup.5b is hydrogen or a
C.sub.1-8 alkyl group, and R.sup.6b is hydrogen, a C.sub.1-8 alkyl
group, or a C.sub.2-8 acyl group;
[0042] each of R.sup.2b and R.sup.3b independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms;
[0043] R.sup.4b is hydrogen, a C.sub.1-8 alkyl group, an alkoxy
group, a C.sub.1-8 alkyl group having one or more halogen atoms, a
halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano,
a C.sub.6-10 aryl group, or a five-membered or six-membered
heterocyclic group; and
[0044] R.sup.7b is a C.sub.1-8 alkyl group.
[0045] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (IVb) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00008##
wherein X.sup.c is O, S, or NH;
[0046] R.sup.1c is hydrogen, a halogen atom, a C.sub.1-8 alkyl
group, a C.sub.1-8 alkoxy group, hydroxyl, tetrazolyl,
N(R.sup.5c)(R.sup.6c), a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl group having one or more halogen
atoms, a C.sub.1-8 alkoxy group having one or more halogen atoms,
or a C.sub.6-10 aryl group, wherein R.sup.5c is hydrogen or a
C.sub.1-8 alkyl group, and R.sup.6c is hydrogen, a C.sub.1-8 alkyl
group, or a C.sub.2-8 acyl group;
[0047] each of R.sup.2c and R.sup.3c independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms;
[0048] R.sup.4c is hydrogen, a C.sub.1-8 alkyl group, an alkoxy
group, a C.sub.1-8 alkyl group having one or more halogen atoms, a
halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano,
a C.sub.6-10 aryl group, or a five-membered or six-membered
heterocyclic group;
[0049] R.sup.7c is hydrogen or a C.sub.1-8 alkyl group; and
[0050] R.sup.8c is hydrogen, a C.sub.1-8 alkyl group, or a
C.sub.2-8 acyl group.
[0051] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (V) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00009##
wherein X is O, S, or NH;
[0052] Y is N or NR.sup.6, wherein R.sup.6 is hydrogen or a
C.sub.1-8 alkyl group;
[0053] R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an alkyl group having phenyl;
[0054] R.sup.2 is a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms,
hydroxyl, nitro, amino, carboxyl, tetrazolyl, or cyano;
[0055] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl,
tetrazolyl, or cyano;
[0056] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms;
[0057] m is 1 or 2;
[0058] when Y is N, the double line consisting of a solid line and
a broken line is a double bond; and
[0059] when Y is NR.sup.6, the double line consisting of a solid
line and a broken line is a single bond.
[0060] The invention further relates to An agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (Va) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00010##
wherein R.sup.11 is hydrogen or a C.sub.1-8 alkyl group;
[0061] R.sup.21 is a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms,
or hydroxyl; and
[0062] R.sup.31 is hydrogen or a halogen atom.
[0063] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (VI) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00011##
wherein A is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0064] B is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0065] X is a C.sub.1-5 alkylene group or a bond;
[0066] Y is a C.sub.1-5 alkylene optionally comprising a double
bond;
[0067] Z is O, S, N(R.sup.5), or a bond, wherein R.sup.5 is
hydrogen or a C.sub.1-8 alkyl group;
[0068] each of R.sup.1, R.sup.2, and R.sup.3 independently is
hydrogen, a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group
having one to three halogen atoms;
[0069] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, a three-membered to
seven-membered cycloalkyl group, or a C.sub.1-8 alkyl group having
a three-membered to seven-membered cycloalkyl group; and
[0070] each of n and m independently is 1 or 2;
[0071] provided that the substituent of the aryl group represented
by A is not an alkyl group when X is a bond.
[0072] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (VIa) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00012##
wherein A.sup.1 is phenyl or thienyl, each of which optionally has
one to three substituents selected from the group consisting of a
halogen atom, a C.sub.1-8 alkyl group having one to three halogen
atoms, nitro, cyano, hydroxyl, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-16 dialkylamino group, a C.sub.2-8 acylamino group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group having one to
three halogen atoms, an aryl group, and a heterocyclic group;
[0073] B.sup.1 is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0074] Y.sup.1 is a C.sub.1-5 alkylene chain optionally comprising
a double bond;
[0075] Z.sup.1 is O, S, N(R.sup.7), or a bond, wherein R.sup.7 is
hydrogen or a C.sub.1-8 alkyl group; and
[0076] R.sup.6 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, or a three-membered
to seven-membered cycloalkyl group.
[0077] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (VIb) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00013##
wherein A.sup.2 is phenyl or thienyl, each of which optionally has
one to three substituents selected from the group consisting of a
halogen atom, a C.sub.1-8 alkyl group having one to three halogen
atoms, nitro, cyano, acetylamino, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkoxy group having one to three halogen atoms, an aryl
group, and a heterocyclic group;
[0078] B.sup.2 is phenyl, naphthyl, benzofuranyl,
1,3-benzo[d]dioxolyl, quinolyl, indolyl, benzothienyl, thienyl, or
pyridyl, each of which optionally has one to three substituents
selected from the group consisting of a halogen atom, a C.sub.1-8
alkyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, nitro, cyano, hydroxyl, amino, a C.sub.2-8 acylamino group,
a C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group having one to
three halogen atoms, a C.sub.6-12 aryloxy group, sulfamoyl, a
C.sub.1-8 alkylsulfamoyl group, and a C.sub.2-16 dialkylsulfamoyl
group;
[0079] Z.sup.2 is O, S, or NH; and
[0080] R.sup.8 is hydrogen or a C.sub.1-8 alkyl group.
[0081] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (VII) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00014##
wherein B is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0082] Y is a C.sub.1-5 alkylene optionally comprising a double
bond;
[0083] Z is O, S, N(R.sup.5), or a bond, wherein R.sup.5 is
hydrogen or a C.sub.1-8 alkyl group;
[0084] each of R.sup.1, R.sup.2, and R.sup.3 independently is
hydrogen, a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group
having one to three halogen atoms;
[0085] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, a three-membered to
seven-membered cycloalkyl group, or a C.sub.1-8 alkyl group having
a three-membered to seven-membered cycloalkyl group;
[0086] each of P and Q independently is hydrogen, a halogen atom, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, nitro, cyano, hydroxyl, amino, a C.sub.1-8
alkylamino group, a C.sub.2-16 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group
having one to three halogen atoms, or a heterocyclic group;
[0087] W is a C.sub.1-8 alkyl group or a three-membered to
seven-membered cycloalkyl group; or
[0088] P and W are combined to form propylene or tetramethylene
when P and W are placed at 2- and 3-positions or 3- and 4-positions
of phenyl; and
[0089] each of n and m independently is 1 or 2.
[0090] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (VIII) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00015##
wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0091] R.sup.2 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0092] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, carboxyl, a
C.sub.2-8 acyl group, or an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety; and
[0093] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms.
[0094] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
compound having the following formula (IX) or a pharmacologically
acceptable salt thereof as an active ingredient:
##STR00016##
wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0095] each of R.sup.2 and R.sup.3 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl
group having one to three halogen atoms, a C.sub.1-8 alkoxy group
having one to three halogen atoms, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.2-8
dialkylamino group, a C.sub.2-8 acylamino group, a C.sub.2-8
acylamino group having one to three halogen atoms, a C.sub.1-8
alkylsulfonylamino group, carboxyl, a C.sub.2-8 acyl group, an
alkoxycarbonyl group comprising a C.sub.1-8 alkoxy moiety,
carbamoyl, a C.sub.1-8 alkylthio group, a C.sub.1-8 alkylsulfinyl
group, a C.sub.1-8 alkylsulfonyl group, or sulfamoyl;
[0096] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, or a C.sub.1-3 alkyl group having phenyl; and
[0097] W is a five-membered or six-membered heterocyclic ring
optionally having one or more substituents and comprising one to
four nitrogen atoms as the members of the ring.
[0098] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing
5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]dia-
zepine-2,4(3H,5H)-dione sodium salt as an active ingredient.
[0099] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing
paroxetine or a pharmacologically acceptable salt thereof as an
active ingredient.
[0100] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
diazepine derivative having the following formula (X) or a
pharmacologically acceptable salt thereof as an active
ingredient:
##STR00017##
wherein each of R.sup.1 and R.sup.2 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0101] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0102] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0103] R.sup.6 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0104] the ring shown below is a five-membered to eight-membered
non-aromatic ring optionally comprising one or two heteroatoms
selected from N, S, and O, and being condensed with the benzene
ring at 1- and 2-positions of the benzene ring;
##STR00018##
[0105] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, thiophene ring,
pyridine ring, pyrimidine ring, indole ring, indazole ring,
benzotriazole ring, benzisoxazole ring, benzimidazole ring, and
quinoline ring;
##STR00019##
[0106] Z is O or S;
[0107] when X is N, Y is C.dbd.O or C.dbd.S, and the double line
consisting of a solid line and a broken line is a single bond;
and
[0108] when X is C, Y is N, and the double line consisting of a
solid line and a broken line is a double bond.
[0109] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
diazepine derivative having the following formula (Xa) or a
pharmacologically acceptable salt thereof as an active
ingredient:
##STR00020##
wherein each of R.sup.11 and R.sup.12 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0110] R.sup.13 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0111] each of R.sup.14 and R.sup.15 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0112] R.sup.16 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0113] the ring shown below is a five-membered to eight-membered
non-aromatic ring optionally comprising one or two heteroatoms
selected from N, S, and O, and being condensed with the benzene
ring at 1- and 2-positions of the benzene ring;
##STR00021##
[0114] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, thiophene ring,
pyridine ring, pyrimidine ring, indole ring, indazole ring,
benzotriazole ring, benzisoxazole ring, benzimidazole ring, and
quinoline ring; and
##STR00022##
[0115] each of Z.sup.1 and Z.sup.2 independently is O or S.
[0116] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
diazepine derivative having the following formula (Xb) or a
pharmacologically acceptable salt thereof as an active
ingredient:
##STR00023##
wherein each of R.sup.21 and R.sup.22 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0117] R.sup.23 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0118] each of R.sup.24 and R.sup.25 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0119] R.sup.26 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents; and
[0120] p is 0 or 1.
[0121] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
diazepine derivative having the following formula (XI) or a
pharmacologically acceptable salt thereof as an active
ingredient:
##STR00024##
wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0122] R.sup.2 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0123] each of R.sup.3 and R.sup.4 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0124] R.sup.5 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino group
having one to five halogen atoms, a C.sub.2-8 dialkylamino group, a
C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group having one
to three halogen atoms, a C.sub.1-8 alkylsulfonylamino group,
carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0125] X is C or N;
[0126] the ring shown below is a heterocyclic ring selected from
the group consisting of thiophene ring, pyridine ring, pyrimidine
ring, quinoline ring, indole ring, indoline ring, benzimidazole
ring, indazole ring, benzisoxazole ring, and benzotriazole ring,
and the ring is combined with X at the carbon atom contained in the
heterocyclic ring as the member of the ring
##STR00025##
[0127] Z is O or S;
[0128] when X is N, Y is C.dbd.O or C.dbd.S, and the double line
consisting of a solid line and a broken line is a single bond;
and
[0129] when X is C, Y is N, and the double line consisting of a
solid line and a broken line is a double bond.
[0130] The invention further relates to an agent for preventing or
treating zoster-associated pain in acute phase containing a
diazepine derivative having the following formula (XIa) or a
pharmacologically acceptable salt thereof as an active
ingredient:
##STR00026##
wherein R.sup.11 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0131] each of R.sup.13 and R.sup.14 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0132] R.sup.15 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino group
having one to five halogen atoms, a C.sub.2-8 dialkylamino group, a
C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group having one
to three halogen atoms, a C.sub.1-8 alkylsulfonylamino group,
carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
and
[0133] the ring shown below is a heterocyclic ring selected from
the group consisting of thiophene ring, pyridine ring, pyrimidine
ring, quinoline ring, indole ring, indoline ring, benzimidazole
ring, indazole ring, benzisoxazole ring, and benzotriazole ring,
and the ring is combined with X at the carbon atom contained in the
heterocyclic ring as the member of the ring;
##STR00027##
[0134] The invention further relates to a compound having the
following formula (XII) or a pharmacologically acceptable salt
thereof:
##STR00028##
wherein each of R.sup.1 and R.sup.2 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0135] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0136] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, an aralkyl group comprising a
C.sub.6-10 aryl moiety and a C.sub.1-3 alkylene moiety, a C.sub.1-8
alkyl group having hydroxyl, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino
group having one to five halogen atoms, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, benzenesulfonylamino optionally having one or more
substituents, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl
group comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0137] the ring shown below is a five-membered to eight-membered
ring optionally comprising one or more heteroatoms selected from N,
S, and O as the members of the ring, and being condensed with the
benzene ring at 1- and 2-positions of the benzene ring; and
##STR00029##
[0138] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, pyridine ring,
pyrimidine ring, quinoline ring, indole ring, indoline ring,
benzimidazole ring, indazole ring, benzisoxazole ring, and
benzotriazole ring.
##STR00030##
[0139] The invention further relates to a compound having the
following formula (XIIa) or a pharmacologically acceptable salt
thereof:
##STR00031##
wherein each of R.sup.11 and R.sup.12 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0140] R.sup.13 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0141] R.sup.14 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, an aralkyl group comprising a
C.sub.6-10 aryl moiety and a C.sub.1-3 alkylene moiety, a C.sub.1-8
alkyl group having hydroxyl, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino
group having one to five halogen atoms, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, benzenesulfonylamino optionally having one or more
substituents, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl
group comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents; and
[0142] the ring shown below is naphthalene ring,
tetrahydronaphthalene ring, or indan ring.
##STR00032##
[0143] The invention further relates to a compound having the
following formula (XIII) or a pharmacologically acceptable salt
thereof:
##STR00033##
wherein each of R.sup.1 and R.sup.2 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0144] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0145] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, an aralkyl group comprising a
C.sub.6-10 aryl moiety and a C.sub.1-3 alkylene moiety, a C.sub.1-8
alkyl group having hydroxyl, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino
group having one to five halogen atoms, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, benzenesulfonylamino optionally having one or more
substituents, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl
group comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0146] the ring shown below is a five-membered to eight-membered
ring optionally comprising one or two nitrogen atoms as the members
of the ring, and being condensed with the benzene ring at 1- and
2-positions of the benzene ring; and
##STR00034##
[0147] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, pyridine ring,
pyrimidine ring, quinoline ring, indole ring, indoline ring,
benzimidazole ring, pyrazole ring, indazole ring, benzisoxazole
ring, and benzotriazole ring;
##STR00035##
[0148] provided that R.sup.4 is not hydrogen, a C.sub.1-8 alkyl
group, or a halogen atom in the case that the ring shown below is
benzene ring.
##STR00036##
[0149] The invention further relates to a compound having the
following formula (XIIIa) or a pharmacologically acceptable salt
thereof:
##STR00037##
wherein each of R.sup.11 and R.sup.12 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0150] R.sup.13 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0151] R.sup.14 is a C.sub.2-8 alkenyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, an
aralkyl group comprising a C.sub.6-10 aryl moiety and a C.sub.1-3
alkylene moiety, a C.sub.1-8 alkyl group having hydroxyl, hydroxyl,
nitro, cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5
alkylamino group having one to five halogen atoms, a C.sub.2-8
dialkylamino group, a C.sub.2-8 acylamino group, a C.sub.2-8
acylamino group having one to three halogen atoms, a C.sub.1-8
alkylsulfonylamino group, benzenesulfonylamino optionally having
one or more substituents, carboxyl, a C.sub.2-8 acyl group, an
alkoxycarbonyl group comprising a C.sub.1-8 alkoxy moiety,
carbamoyl, a C.sub.1-8 alkylthio group, a C.sub.1-8 alkylsulfinyl
group, a C.sub.1-8 alkylsulfonyl group, sulfamoyl, phenyl
optionally having one or more substituents, or a heterocyclic group
optionally having one or more substituents; and
[0152] the ring shown below is naphthalene ring,
tetrahydronaphthalene ring, or indan ring.
##STR00038##
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0153] FIG. 1 shows fluorescent double immunohistostaining images
within the posterior horn area of spinal L5 after HSV-1 virus
infection in Example 2.
[0154] The cells positive to both the OX42 antibody, which is
expressed specific to the microglia, and the P2X.sub.4 receptor
antibody are brightly shown (the area indicated by the arrow and
the area circled with the dotted line).
[0155] The right figures show HSV-1 virus inoculation, and the left
figures show non-virus inoculation.
[0156] The upper figures show the whole image of the spinal
posterior horn, and the lower figures show the enlarged image.
[0157] FIG. 2 is a graph showing the results of the RT-real time
PCR analysis using Iba1 protein mRNA expression changes caused by
herpes zoster manifestation in Example 2.
[0158] FIG. 3 is a graph showing the results of RT-real time PCR
analysis of mRNA expression of P2X.sub.4 receptor protein caused by
herpes zoster manifestation in Example 2.
[0159] FIG. 4 is graphs showing influences of oral administration
of paroxetine on acute phase pain of herpes zoster in Example
3.
[0160] The right is a graph showing the influences of paroxetine
seven days after virus inoculation, and the left is a graph showing
the influences of paroxetine thirty 30 days after virus
inoculation.
[0161] FIG. 5 is a graph showing the effect of the compound A on
zoster-associated pain in acute phase in Example 4.
THE EMBODIMENTS OF THE INVENTION
[0162] The present invention is described below in more detail.
[0163] The active ingredients of the agent of the invention for
preventing or treating zoster-associated pain in acute phase
include the following compounds.
(1) P2X.sub.4 receptor antagonist. (2) A compound having the
following formula (I) or a pharmacologically acceptable salt
thereof:
##STR00039##
wherein R.sup.1 is a halogen atom; and
[0164] R.sup.2 is hydrogen, a halogen atom, nitro, cyano,
--C(O)OR.sup.3, --C(O)--NR.sup.4R.sup.5, --SO.sub.2--OR.sup.3, or
--SO.sub.2--NR.sup.4R.sup.5, wherein each of R.sup.3, R.sup.4, and
R.sup.5 is hydrogen or a C.sub.1-6 alkyl group; or in the
alternative
[0165] R.sup.1 is hydrogen; and
[0166] R.sup.2 is a halogen atom, nitro, cyano, --C(O)--OR.sup.3,
--C(O)--NR.sup.4R.sup.5, --SO.sub.2--OR.sup.3, or
--SO.sub.2--NR.sup.4R.sup.5, wherein each of R.sup.3, R.sup.4, and
R.sup.5 is hydrogen or a C.sub.1-6 alkyl group.
(3) A compound having the formula (I) described in (2) or a
pharmacologically acceptable salt thereof: wherein R.sup.1 is
chloro or bromo; and
[0167] R.sup.2 is hydrogen, chloro, bromo, nitro, cyano, or
--C(O)--OR.sup.3, or --C(O)--NR.sup.4R.sup.5, wherein each of
R.sup.3, R.sup.4, and R.sup.5 is hydrogen or a C.sub.1-4 alkyl
group; or in the alternative
[0168] R.sup.1 is hydrogen; and
[0169] R.sup.2 is chloro, bromo, nitro, cyano, --C(O)--OR.sup.3, or
--C(O)--NR.sup.4R.sup.5, wherein each of R.sup.3, R.sup.4, and
R.sup.5 is hydrogen or a C.sub.1-4 alkyl group.
(4) A compound having the following formula (Ia) or a
pharmacologically acceptable salt thereof:
##STR00040##
wherein R.sup.1 is chloro or bromo; and
[0170] R.sup.2 is hydrogen, chloro, bromo, nitro, or cyano; or in
the alternative
[0171] R.sup.1 is hydrogen; and
[0172] R.sup.2 is chloro, bromo, nitro, or cyano.
(5) A compound having the following formula (II) or a
pharmacologically acceptable salt thereof:
##STR00041##
wherein R is a C.sub.1-4 alkyl group, a C.sub.2-4 alkynyl group,
phenyl optionally having one or more substituents selected from the
group consisting of a lower alkyl group, an alkylthio group, an
alkoxy group, a halogen atom, nitro, an acylamino group,
methylsulfonyl, and methylenedioxy, or tetrahydronaphthyl;
[0173] R.sup.1 is hydrogen; and
[0174] X is hydrogen, a C.sub.1-4 alkyl group, a trifluoroalkyl
group, hydroxyl, a halogen atom, methylthio, or an arylalkoxy
group.
(6) A selective serotonin reuptake inhibitor. (7) Imipramine,
nortriptyline, amitriptyline, desipramine, doxepin, fluoxetine,
fluvoxamine, citalopram, or a pharmacologically acceptable salt
thereof. (8) A compound having the following formula (III) or a
pharmacologically acceptable salt thereof:
##STR00042##
wherein X is S or CH.sub.2;
[0175] Y is O, S, or NH;
[0176] R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one or more halogen atoms, an aralkyl group
comprising a C.sub.1-6 alkyl moiety and a C.sub.6-10 aryl moiety, a
C.sub.2-8 alkenyl group, carboxymethyl, or an alkoxycarbonylmethyl
group comprising a C.sub.1-8 alkoxy moiety;
[0177] each of R.sup.2 and R.sup.3 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl
group having one or more halogen atoms, a C.sub.1-8 alkoxy group
having one or more halogen atoms, a halogen atom, amino, carboxyl,
hydroxyl, nitro, cyano, a C.sub.2-8 acyl group, a C.sub.6-10 aryl
group, or a five-membered or six-membered heterocyclic group;
[0178] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms; and
[0179] the double line consisting of a broken line and a solid line
is a single bond or a double bond.
(9) A compound having the formula (III) described in (8) or a
pharmacologically acceptable salt thereof, wherein X is S. (10) A
compound having the formula (III) described in (8) or a
pharmacologically acceptable salt thereof, wherein Y is O. (11) A
compound having the formula (III) described in (8) or a
pharmacologically acceptable salt thereof, wherein R.sup.1 is
hydrogen or a C.sub.1-8 alkyl group. (12) A compound having the
formula (III) described in (8) or a pharmacologically acceptable
salt thereof, wherein each of R.sup.2 and R.sup.3 independently is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one or more halogen atoms, a C.sub.1-8
alkoxy group having one or more halogen atoms, a halogen atom,
amino, carboxyl, hydroxyl, nitro, or cyano. (13) A compound having
the formula (III) described in (8) or a pharmacologically
acceptable salt thereof, wherein R.sup.3 is hydrogen, and R.sup.2
is a halogen atom or hydroxyl. (14) A compound having the formula
(III) described in (8) or a pharmacologically acceptable salt
thereof, wherein R.sup.2 substitutes at meta-position. (15) A
compound having the formula (III) described in (8) or a
pharmacologically acceptable salt thereof, wherein each of R.sup.4
and R.sup.5 is hydrogen. (16) A compound having the formula (III)
described in (8) or a pharmacologically acceptable salt thereof,
wherein the double line consisting of a broken line and a solid
line is a double bond. (17) A compound having the following formula
(IV) or a pharmacologically acceptable salt thereof:
##STR00043##
wherein X.sup.a is O, S, or NH;
[0180] R.sup.1a is hydroxyl, tetrazolyl, N(R.sup.5a)(R.sup.6a), a
C.sub.2-8 alkenyl group, a C.sub.2-8 alkynyl group, a C.sub.1-8
alkyl group having one or more halogen atoms, a C.sub.1-8 alkoxy
group having one or more halogen atoms, or a C.sub.6-10 aryl group,
wherein R.sup.5a is hydrogen or a C.sub.1-8 alkyl group, and
R.sup.6a is hydrogen, a C.sub.1-8 alkyl group, or a C.sub.2-8 acyl
group;
[0181] each of R.sup.2a and R.sup.3a independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms; and
[0182] R.sup.4a is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one or more halogen
atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl,
tetrazolyl, cyano, a C.sub.6-10 aryl group, or a five-membered or
six-membered heterocyclic group.
(18) A compound having the formula (IV) described in (17) or a
pharmacologically acceptable salt thereof, wherein X.sup.a is O.
(19) A compound having the formula (IV) described in (17) or a
pharmacologically acceptable salt thereof, wherein R.sup.1a is
hydroxyl, amino, a C.sub.1-8 alkylamino group, a C.sub.2-12
dialkylamino group, a C.sub.1-8 alkyl group having one or more
halogen atoms, or phenyl. (20) A compound having the formula (IV)
described in (17) or a pharmacologically acceptable salt thereof,
wherein R.sup.1a substitutes at meta-position. (21) A compound
having the formula (IV) described in (17) or a pharmacologically
acceptable salt thereof, wherein each of R.sup.2a and R.sup.3a is
hydrogen. (22) A compound having the formula (IV) described in (17)
or a pharmacologically acceptable salt thereof, wherein R.sup.4a is
hydrogen. (23) A compound having the following formula (IVa) or a
pharmacologically acceptable salt thereof:
##STR00044##
wherein X.sup.b is O, S, or NH;
[0183] R.sup.1b is a halogen atom, hydroxyl, tetrazolyl,
N(R.sup.5b)(R.sup.6b), a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl group having one or more halogen
atoms, a C.sub.1-8 alkoxy group having one or more halogen atoms,
or a C.sub.6-10 aryl group, wherein R.sup.5b is hydrogen or a
C.sub.1-8 alkyl group, and R.sup.6b is hydrogen, a C.sub.1-8 alkyl
group, or a C.sub.2-8 acyl group;
[0184] each of R.sup.2b and R.sup.3b independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms;
[0185] R.sup.4b is hydrogen, a C.sub.1-8 alkyl group, an alkoxy
group, a C.sub.1-8 alkyl group having one or more halogen atoms, a
halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano,
a C.sub.6-10 aryl group, or a five-membered or six-membered
heterocyclic group; and
[0186] R.sup.7b is a C.sub.1-8 alkyl group.
(24) A compound having the formula (IVa) described in (23) or a
pharmacologically acceptable salt thereof, wherein X.sup.b is O.
(25) A compound having the formula (IVa) described in (23) or a
pharmacologically acceptable salt thereof, wherein R.sup.1b is a
halogen atom, hydroxyl, amino, a C.sub.1-8 alkylamino group,
dialkylamino group, a C.sub.1-8 alkyl group having one or more
halogen atoms, or phenyl. (26) A compound having the formula (IVa)
described in (23) or a pharmacologically acceptable salt thereof,
wherein R.sup.1b substitutes at meta-position. (27) A compound
having the formula (IVa) described in (23) or a pharmacologically
acceptable salt thereof, wherein each of R.sup.2b and R.sup.3b is
hydrogen. (28) A compound having the formula (IVa) described in
(23) or a pharmacologically acceptable salt thereof, wherein
R.sup.4b is hydrogen. (29) A compound having the following formula
(IVb) or a pharmacologically acceptable salt thereof:
##STR00045##
wherein X.sup.c is O, S, or NH;
[0187] R.sup.1c is hydrogen, a halogen atom, a C.sub.1-8 alkyl
group, a C.sub.1-8 alkoxy group, hydroxyl, tetrazolyl,
N(R.sup.5c)(R.sup.6c), a C.sub.2-8 alkenyl group, a C.sub.2-8
alkynyl group, a C.sub.1-8 alkyl group having one or more halogen
atoms, a C.sub.1-8 alkoxy group having one or more halogen atoms,
or a C.sub.6-10 aryl group, wherein R.sup.5c is hydrogen or a
C.sub.1-8 alkyl group, and R.sup.6c is hydrogen, a C.sub.1-8 alkyl
group, or a C.sub.2-8 acyl group;
[0188] each of R.sup.2c and R.sup.3c independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one or
more halogen atoms;
[0189] R.sup.4c is hydrogen, a C.sub.1-8 alkyl group, an alkoxy
group, a C.sub.1-8 alkyl group having one or more halogen atoms, a
halogen atom, hydroxyl, nitro, amino, carboxyl, tetrazolyl, cyano,
a C.sub.6-10 aryl group, or a five-membered or six-membered
heterocyclic group;
[0190] R.sup.7c is hydrogen or a C.sub.1-8 alkyl group; and
[0191] R.sup.8c is hydrogen, a C.sub.1-8 alkyl group, or a
C.sub.2-8 acyl group.
(30) A compound having the formula (IVb) described in (29) or a
pharmacologically acceptable salt thereof, wherein X.sup.c is O.
(31) A compound having the formula (IVb) described in (29) or a
pharmacologically acceptable salt thereof, wherein R.sup.1c is
hydrogen, a halogen atom, hydroxyl, amino, a C.sub.1-8 alkylamino
group, dialkylamino group, a C.sub.1-8 alkyl group having one or
more halogen atoms, or phenyl. (32) A compound having the formula
(IVb) described in (29) or a pharmacologically acceptable salt
thereof, wherein R.sup.1c substitutes at meta-position. (33) A
compound having the formula (IVb) described in (29) or a
pharmacologically acceptable salt thereof, wherein each of R.sup.2c
and R.sup.3c is hydrogen. (34) A compound having the formula (IVb)
described in (29) or a pharmacologically acceptable salt thereof,
wherein R.sup.4c is hydrogen or a halogen atom. (35) A compound
having the formula (IVb) described in (29) or a pharmacologically
acceptable salt thereof, wherein R.sup.7c is hydrogen. (36) A
compound having the formula (IVb) described in (29) or a
pharmacologically acceptable salt thereof, wherein R.sup.8c is
hydrogen. (37) A compound having the following formula (V) or a
pharmacologically acceptable salt thereof:
##STR00046##
wherein X is O, S, or NH;
[0192] Y is N or NR.sup.6, wherein R.sup.6 is hydrogen or a
C.sub.1-8 alkyl group;
[0193] R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an alkyl group having phenyl;
[0194] R.sup.2 is a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms,
hydroxyl, nitro, amino, carboxyl, tetrazolyl, or cyano;
[0195] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, amino, carboxyl,
tetrazolyl, or cyano;
[0196] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms;
[0197] m is 1 or 2;
[0198] when Y is N, the double line consisting of a solid line and
a broken line is a double bond; and
[0199] when Y is NR.sup.6, the double line consisting of a solid
line and a broken line is a single bond.
(38) A compound having the formula (V) described in (37) or a
pharmacologically acceptable salt thereof, wherein m is 1. (39) A
compound having the formula (V) described in (37) or a
pharmacologically acceptable salt thereof, wherein X is O. (40) A
compound having the formula (V) described in (37) or a
pharmacologically acceptable salt thereof, wherein Y is N. (41) A
compound having the formula (V) described in (37) or a
pharmacologically acceptable salt thereof, wherein R.sup.1 is
hydrogen or a C.sub.1-8 alkyl group. (42) A compound having the
formula (V) described in (37) or a pharmacologically acceptable
salt thereof, wherein R.sup.1 is hydrogen. (43) A compound having
the formula (V) described in (37) or a pharmacologically acceptable
salt thereof, wherein each of R.sup.4 and R.sup.5 is hydrogen. (44)
A compound having the formula (V) described in (37) or a
pharmacologically acceptable salt thereof, wherein R.sup.2 is a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl
group having one to three halogen atoms, or hydroxyl. (45) A
compound having the formula (V) described in (37) or a
pharmacologically acceptable salt thereof, wherein R.sup.2 is a
C.sub.1-8 alkoxy group or hydroxyl. (46) A compound having the
formula (V) described in (37) or a pharmacologically acceptable
salt thereof, wherein R.sup.3 is hydrogen or a halogen atom. (47) A
compound having the formula (V) described in (37) or a
pharmacologically acceptable salt thereof, wherein R.sup.3 is
hydrogen. (48) A compound having the following formula (Va) or a
pharmacologically acceptable salt thereof:
##STR00047##
wherein R.sup.11 is hydrogen or a C.sub.1-8 alkyl group;
[0200] R.sup.21 is a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms,
or hydroxyl; and
[0201] R.sup.31 is hydrogen or a halogen atom.
(49) A compound having the formula (Va) described in (48) or a
pharmacologically acceptable salt thereof, wherein R.sup.11 is
hydrogen. (50) A compound having the formula (Va) described in (48)
or a pharmacologically acceptable salt thereof, wherein R.sup.21 is
a C.sub.1-8 alkoxy group or hydroxyl. (51) A compound having the
formula (Va) described in (48) or a pharmacologically acceptable
salt thereof, wherein R.sup.31 is hydrogen. (52)
5-(3-methoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,
[0202]
5-(3-hydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-o-
ne, [0203]
5-(4-methoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin--
2-one, [0204]
5-(4-hydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,
[0205]
5-(4-methylphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-on-
e, [0206]
5-(2-methoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-
-one, [0207]
5-(2-hydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,
[0208]
5-(3,4-dimethoxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-
-2-one, [0209]
5-(3,4-dihydroxyphenyl)-1,3-dihydro-2H-naphtho[1,2-e]-1,4-diazepin-2-one,
or [0210] a pharmacologically acceptable salt thereof. (53) A
compound having the following formula (VI) or a pharmacologically
acceptable salt thereof:
##STR00048##
[0210] wherein A is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0211] B is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0212] X is a C.sub.1-5 alkylene group or a bond;
[0213] Y is a C.sub.1-5 alkylene optionally comprising a double
bond;
[0214] Z is O, S, N(R.sup.5), or a bond, wherein R.sup.5 is
hydrogen or a C.sub.1-8 alkyl group;
[0215] each of R.sup.1, R.sup.2, and R.sup.3 independently is
hydrogen, a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group
having one to three halogen atoms;
[0216] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, a three-membered to
seven-membered cycloalkyl group, or a C.sub.1-8 alkyl group having
a three-membered to seven-membered cycloalkyl group; and
[0217] each of n and m independently is 1 or 2;
[0218] provided that when X is a bond, the substituent of the aryl
group represented by A is not an alkyl group.
(54) A compound having the formula (VI) described in (53) or a
pharmacologically acceptable salt thereof, wherein A is phenyl or
thienyl, each of which optionally has one to three substituents
selected from the group consisting of a halogen atom, a C.sub.1-8
alkyl group (except that X is a bond), a C.sub.1-8 alkyl group
having one to three halogen atoms, nitro, cyano, hydroxyl, amino, a
C.sub.1-8 alkylamino group, a C.sub.2-16 dialkylamino group, a
C.sub.2-8 acylamino group, a C.sub.1-8 alkoxy group, a C.sub.1-8
alkoxy group having one to three halogen atoms, an aryl group, and
a heterocyclic group. (55) A compound having the formula (VI)
described in (53) or a pharmacologically acceptable salt thereof,
wherein A is phenyl optionally having one to three substituents
selected from the group consisting of selected from the group
consisting of a halogen atom, a C.sub.1-8 alkyl group (except that
X is a bond), a C.sub.1-8 alkoxy group, and a C.sub.1-8 alkyl group
having one to three halogen atoms. (56) A compound having the
formula (VI) described in (53) or a pharmacologically acceptable
salt thereof, wherein B is phenyl, naphthyl, benzofuranyl,
1,3-benzo[d]dioxolyl, quinolyl, indolyl, benzothienyl, thienyl, or
pyridyl, each of which optionally has one to three substituents
selected from the group consisting of a halogen atom, a C.sub.1-8
alkyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, nitro, cyano, hydroxyl, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-16 dialkylamino group, a C.sub.2-8 acylamino group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group having one to
three halogen atoms, a C.sub.6-12 aryloxy group, a C.sub.2-9
alkoxycarbonyl group, carbamoyl, a C.sub.2-9 alkylcarbamoyl group,
sulfamoyl, a C.sub.1-8 alkylsulfamoyl group, and a C.sub.2-16
dialkylsulfamoyl group. (57) A compound having the formula (VI)
described in (53) or a pharmacologically acceptable salt thereof,
wherein B is phenyl, naphthyl, benzofuranyl, or
1,3-benzo[d]dioxolyl, each of which optionally has one to three
substituents selected from the group consisting of a halogen atom,
a C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to
three halogen atoms, a C.sub.1-8 alkoxy group, a C.sub.6-12 aryloxy
group, sulfamoyl, a C.sub.1-8 alkylsulfamoyl group, and a
C.sub.2-16 dialkylsulfamoyl group. (58) A compound having the
formula (VI) described in (53) or a pharmacologically acceptable
salt thereof, wherein X is a bond. (59) A compound having the
formula (VI) described in (53) or a pharmacologically acceptable
salt thereof, wherein Y is methylene. (60) A compound having the
formula (VI) described in (53) or a pharmacologically acceptable
salt thereof, wherein Z is O or S. (61) A compound having the
formula (VI) described in (53) or a pharmacologically acceptable
salt thereof, wherein each of R.sup.1, R.sup.2, and R.sup.3 is
hydrogen. (62) A compound having the formula (VI) described in (53)
or a pharmacologically acceptable salt thereof, wherein R.sup.4 is
hydrogen or a C.sub.1-8 alkyl group. (63) A compound having the
formula (VI) described in (53) or a pharmacologically acceptable
salt thereof, wherein R.sup.4 is hydrogen. (64) A compound having
the formula (VI) described in (53) or a pharmacologically
acceptable salt thereof, wherein each of n and m is 1. (65) A
compound having the following formula (VIa) or a pharmacologically
acceptable salt thereof:
##STR00049##
wherein A.sup.1 is phenyl or thienyl, each of which optionally has
one to three substituents selected from the group consisting of a
halogen atom, a C.sub.1-8 alkyl group having one to three halogen
atoms, nitro, cyano, hydroxyl, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-16 dialkylamino group, a C.sub.2-8 acylamino group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group having one to
three halogen atoms, an aryl group, and a heterocyclic group;
[0219] B.sup.1 is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0220] Y.sup.1 is a C.sub.1-5 alkylene chain optionally comprising
a double bond;
[0221] Z.sup.1 is O, S, N(R.sup.7), or a bond, wherein R.sup.7 is
hydrogen or a C.sub.1-8 alkyl group; and
[0222] R.sup.6 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, or a three-membered
to seven-membered cycloalkyl group.
(66) A compound having the formula (VIa) described in (65) or a
pharmacologically acceptable salt thereof, wherein A.sup.1 is
phenyl optionally having one to three substituents selected from
the group consisting of a halogen atom, a C.sub.1-8 alkyl group
having one to three halogen atoms, and a C.sub.1-8 alkoxy group.
(67) A compound having the formula (VIa) described in (65) or a
pharmacologically acceptable salt thereof, wherein B.sup.1 is
phenyl, naphthyl, benzofuranyl, 1,3-benzo[d]dioxolyl, quinolyl,
indolyl, benzothienyl, thienyl, or pyridyl, each of which
optionally has one to three substituents selected from the group
consisting of a halogen atom, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, nitro, cyano,
hydroxyl, amino, a C.sub.1-8 alkylamino group, a C.sub.2-16
dialkylamino group, a C.sub.2-8 acylamino group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a C.sub.6-12 aryloxy group, a C.sub.2-9 alkoxycarbonyl group,
carbamoyl, a C.sub.2-9 alkylcarbamoyl group, sulfamoyl, a C.sub.1-8
alkylsulfamoyl group and a C.sub.2-16 dialkylsulfamoyl group. (68)
A compound having the formula (VIa) described in (65) or a
pharmacologically acceptable salt thereof, wherein B.sup.1 is
phenyl, naphthyl, benzofuranyl, or 1,3-benzo[d]dioxolyl. (69) A
compound having the formula (VIa) described in (65) or a
pharmacologically acceptable salt thereof, wherein Y.sup.1 is
methylene. (70) A compound having the formula (VIa) described in
(65) or a pharmacologically acceptable salt thereof, wherein
Z.sup.1 is O or S. (71) A compound having the formula (VIa)
described in (65) or a pharmacologically acceptable salt thereof,
wherein R.sup.6 is hydrogen or a C.sub.1-8 alkyl group. (72) A
compound having the formula (VIa) described in (65) or a
pharmacologically acceptable salt thereof, wherein R.sup.6 is
hydrogen. (73) A compound having the following formula (VIb) or a
pharmacologically acceptable salt thereof:
##STR00050##
wherein A.sup.2 is phenyl or thienyl, each of which optionally has
one to three substituents selected from the group consisting of a
halogen atom, a C.sub.1-8 alkyl group having one to three halogen
atoms, nitro, cyano, acetylamino, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkoxy group having one to three halogen atoms, an aryl
group, and a heterocyclic group;
[0223] B.sup.2 is phenyl, naphthyl, benzofuranyl,
1,3-benzo[d]dioxolyl, quinolyl, indolyl, benzothienyl, thienyl, or
pyridyl, each of which optionally has one to three substituents
selected from the group consisting of a halogen atom, a C.sub.1-8
alkyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, nitro, cyano, hydroxyl, amino, a C.sub.2-8 acylamino group,
a C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group having one to
three halogen atoms, a C.sub.6-12 aryloxy group, sulfamoyl, a
C.sub.1-8 alkylsulfamoyl group, and a C.sub.2-16 dialkylsulfamoyl
group;
[0224] Z.sup.2 is O, S, or NH; and
[0225] R.sup.8 is hydrogen or a C.sub.1-8 alkyl group.
(74) A compound having the formula (VIb) described in (73) or a
pharmacologically acceptable salt thereof, wherein A.sup.2 is
phenyl optionally having one to three substituents selected from
the group consisting of a halogen atom, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group, nitro,
cyano, or acetylamino. (75) A compound having the formula (VIb)
described in (73) or a pharmacologically acceptable salt thereof,
wherein A.sup.2 is phenyl optionally having one to three
substituents selected from the group consisting of a halogen atom,
a C.sub.1-8 alkyl group having one to three halogen atoms, and a
C.sub.1-8 alkoxy group. (76) A compound having the formula (VIb)
described in (73) or a pharmacologically acceptable salt thereof,
wherein B.sup.2 is phenyl, naphthyl, benzofuranyl, or
1,3-benzo[d]dioxolyl, each of which optionally has one to three
substituents selected from the group consisting of a halogen atom,
a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms, an aryloxy group, sulfamoyl, a C.sub.1-8
alkylsulfamoyl group, and a C.sub.2-16 dialkylsulfamoyl group. (77)
A compound having the formula (VIb) described in (73) or a
pharmacologically acceptable salt thereof, wherein Z.sup.2 is O or
S. (78) A compound having the formula (VIb) described in (73) or a
pharmacologically acceptable salt thereof, wherein R.sup.8 is
hydrogen. (79)
1-(4-fluorophenyl)-2-(4-phenoxyphenoxymethyl)piperazine, [0226]
1-(4-fluorophenyl)-2-(4-phenoxyphenylsulfanylmethyl)piperazine,
[0227] 2-(4-chlorophenoxymethyl)-1-(4-isopropoxyphenyl)piperazine,
[0228]
2-(2,4-dichlorophenoxymethyl)-1-(4-isopropoxyphenyl)piperazine,
[0229]
2-(4-tert-butoxyphenoxymethyl)-1-(4-isopropoxyphenyl)piperazine,
[0230] 2-(4-chlorophenoxymethyl)-1-(3-methoxyphenyl)piperazine,
[0231] 2-(4-chlorophenoxymethyl)-1-(2-methoxyphenyl)piperazine, or
[0232] a pharmacologically acceptable salt thereof. (80) A compound
having the following formula (VII) or a pharmacologically
acceptable salt thereof:
##STR00051##
[0232] wherein B is an aryl group optionally having one or more
substituents or a heterocyclic group optionally having one or more
substituents;
[0233] Y is a C.sub.1-5 alkylene optionally comprising a double
bond;
[0234] Z is O, S, N(R.sup.5), or a bond, wherein R.sup.5 is
hydrogen or a C.sub.1-8 alkyl group;
[0235] each of R, R.sup.2, and R.sup.3 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms;
[0236] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, a three-membered to
seven-membered cycloalkyl group, or a C.sub.1-8 alkyl group having
a three-membered to seven-membered cycloalkyl group;
[0237] each of P and Q independently is hydrogen, a halogen atom, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, nitro, cyano, hydroxyl, amino, a C.sub.1-8
alkylamino group, a C.sub.2-16 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group
having one to three halogen atoms, or a heterocyclic group;
[0238] W is a C.sub.1-8 alkyl group or a three-membered to
seven-membered cycloalkyl group; or
[0239] when P and W are placed at 2- and 3-positions or 3- and
4-positions of phenyl, P and W are combined to form propylene or
tetramethylene; and
[0240] each of n and m independently is 1 or 2.
(81) A compound having the formula (VII) described in (80) or a
pharmacologically acceptable salt thereof, wherein B is phenyl,
naphthyl, benzofuranyl, indolyl, benzothienyl, or thienyl
optionally having one to three substituents selected from the group
consisting of a halogen atom, a C.sub.1-8 alkyl group, a C.sub.1-8
alkyl group having one to three halogen atoms, nitro, cyano,
hydroxyl, amino, a C.sub.1-8 alkylamino group, a C.sub.2-16
dialkylamino group, a C.sub.2-8 acylamino group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a C.sub.6-12 aryloxy group, an arylalkoxy group comprising a
C.sub.1-8 alkyl moiety, a C.sub.2-9 alkoxycarbonyl group,
carbamoyl, a C.sub.2-9 alkylcarbamoyl group, sulfamoyl, a C.sub.1-8
alkylsulfamoyl group, and a C.sub.2-16 dialkylsulfamoyl group. (82)
A compound having the formula (VII) described in (80) or a
pharmacologically acceptable salt thereof, wherein B is phenyl
optionally having one to three substituents selected from the group
consisting of selected from the group consisting of a halogen atom,
a C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to
three halogen atoms, nitro, cyano, hydroxyl, amino, a C.sub.1-8
alkylamino group, a C.sub.2-16 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkoxy group
having one to three halogen atoms, a C.sub.6-12 aryloxy group, an
arylalkoxy group comprising a C.sub.1-8 alkyl moiety, a C.sub.2-9
alkoxycarbonyl group, carbamoyl, a C.sub.2-9 alkylcarbamoyl group,
sulfamoyl, a C.sub.1-8 alkylsulfamoyl group, and a C.sub.2-16
dialkylsulfamoyl group. (83) A compound having the formula (VII)
described in (80) or a pharmacologically acceptable salt thereof,
wherein each of P and Q independently is hydrogen, a C.sub.1-8
alkyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-8 alkoxy group. (84) A compound having the
formula (VII) described in (80) or a pharmacologically acceptable
salt thereof, wherein each of P and Q is hydrogen. (85) A compound
having the formula (VII) described in (80) or a pharmacologically
acceptable salt thereof, wherein W is a C.sub.3-6 alkyl group. (86)
A compound having the formula (VII) described in (80) or a
pharmacologically acceptable salt thereof, wherein W is n-propyl,
isopropyl, n-butyl, or isobutyl. (87) A compound having the formula
(VII) described in (80) or a pharmacologically acceptable salt
thereof, wherein each of n and m is 1. (88) A compound having the
formula (VII) described in (80) or a pharmacologically acceptable
salt thereof, wherein Y is methylene. (89) A compound having the
formula (VII) described in (80) or a pharmacologically acceptable
salt thereof, wherein Z is O or S. (90) A compound having the
formula (VII) described in (80) or a pharmacologically acceptable
salt thereof, wherein each of R.sup.1, R.sup.2, and R.sup.3 is
hydrogen. (91) A compound having the formula (VII) described in
(80) or a pharmacologically acceptable salt thereof, wherein
R.sup.4 is hydrogen or a C.sub.1-8 alkyl group. (92) A compound
having the formula (VII) described in (80) or a pharmacologically
acceptable salt thereof, wherein R.sup.4 is hydrogen. (93) A
compound having the formula (VII) described in (80) or a
pharmacologically acceptable salt thereof: wherein R.sup.4 is
hydrogen;
[0241] Y is methylene;
[0242] Z is O or S; and
[0243] B is phenyl optionally having one to three substituents
selected from the group consisting of a halogen atom, a C.sub.1-8
alkyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, cyano, hydroxyl, a C-s alkoxy group, a C.sub.1-8 alkoxy
group having one to three halogen atoms, benzyloxy, sulfamoyl, and
a C.sub.1-8 alkylsulfamoyl group.
(94) 2-(4-chlorophenoxymethyl)-1-(4-isopropylphenyl)piperazine,
2-(4-chlorophenoxymethyl)-1-(4-propylphenyl)piperazine, [0244]
2-(4-chlorophenoxymethyl)-1-(3-isopropylphenyl)piperazine, [0245]
2-(4-chlorophenoxymethyl)-1-(2,4,6-trimethylphenyl)piperazine,
[0246] 2-(4-chlorophenoxymethyl)-1-indan-5-yl-piperazine, [0247]
1-(4-isopropylphenyl)-2-[4-(isopropylsulfamoyl)phenoxymethyl]piperazine,
[0248]
2-(4-chlorophenylsulfanylmethyl)-1-(4-isopropylphenyl)piperazine,
[0249]
1-(3-isopropylphenyl)-2-[4-(isopropylsulfamoyl)phenoxymethyl]piper-
azine, [0250]
1-(4-isopropylphenyl)-2-(4-phenoxyphenoxymethyl)piperazine, or
[0251] a pharmacologically acceptable salt thereof. (95) A compound
having the following formula (VIII) or a pharmacologically
acceptable salt thereof:
##STR00052##
[0251] wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a
C.sub.2-8 alkenyl group, a C.sub.1-8 alkyl group having one to
three halogen atoms, or a C.sub.1-3 alkyl group having phenyl;
[0252] R.sup.2 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0253] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, carboxyl, a
C.sub.2-8 acyl group, or an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety; and
[0254] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms.
(96) A compound having the formula (VIII) described in (95) or a
pharmacologically acceptable salt thereof, wherein R.sup.1 is
hydrogen or a C.sub.1-8 alkyl group. (97) A compound having the
formula (VIII) described in (95) or a pharmacologically acceptable
salt thereof, wherein R.sup.1 is hydrogen. (98) A compound having
the formula (VIII) described in (95) or a pharmacologically
acceptable salt thereof, wherein R.sup.4 is hydrogen, and R.sup.5
is hydrogen or a C.sub.1-8 alkyl group. (99) A compound having the
formula (VIII) described in (95) or a pharmacologically acceptable
salt thereof, wherein each of R.sup.4 and R.sup.5 is hydrogen.
(100) A compound having the formula (VIII) described in (95) or a
pharmacologically acceptable salt thereof, wherein R.sup.2 is a
C.sub.1-8 alkoxy group, hydroxyl, carboxyl, cyano, or an
alkoxycarbonyl group comprising a C.sub.1-8 alkoxy moiety. (101) A
compound having the formula (VIII) described in (95) or a
pharmacologically acceptable salt thereof, wherein R.sup.2 is a
C.sub.1-8 alkoxy group or hydroxyl. (102) A compound having the
formula (VIII) described in (95) or a pharmacologically acceptable
salt thereof, wherein R.sup.3 is hydrogen. (103) A compound having
the following formula (IX) or a pharmacologically acceptable salt
thereof:
##STR00053##
wherein R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0255] each of R.sup.2 and R.sup.3 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl
group having one to three halogen atoms, a C.sub.1-8 alkoxy group
having one to three halogen atoms, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.2-8
dialkylamino group, a C.sub.2-8 acylamino group, a C.sub.2-8
acylamino group having one to three halogen atoms, a C.sub.1-8
alkylsulfonylamino group, carboxyl, a C.sub.2-8 acyl group, an
alkoxycarbonyl group comprising a C.sub.1-8 alkoxy moiety,
carbamoyl, a C.sub.1-8 alkylthio group, a C.sub.1-8 alkylsulfinyl
group, a C.sub.1-8 alkylsulfonyl group, or sulfamoyl;
[0256] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, or a C.sub.1-3 alkyl group having phenyl; and
[0257] W is a five-membered or six-membered heterocyclic ring
optionally having one or more substituents and comprising one to
four nitrogen atoms as the members of the ring.
(104) A compound having the formula (IX) described in (103) or a
pharmacologically acceptable salt thereof, wherein W is tetrazole,
1,2,4-triazole, 1,2,3-triazole, 1,2,4-oxadiazole, pyrazole, or
imidazole, each of which optionally has one or more substituents
selected from the group consisting of a C.sub.1-8 alkyl group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a halogen
atom, cyano, oxo, and thioxo. (105) A compound having the formula
(IX) described in (103) or a pharmacologically acceptable salt
thereof, wherein W is tetrazole, 1,2,4-triazole, or 1,2,3-triazole,
each of which optionally has one or more substituents selected from
the group consisting of a C.sub.1-8 alkyl group, a C.sub.1-8 alkyl
group having one to three halogen atoms, a halogen atom, and cyano.
(106) A compound having the formula (IX) described in (103) or a
pharmacologically acceptable salt thereof, wherein W is
5-oxo-1,2,4-oxadiazole or 5-thioxo-1,2,4-oxadiazole. (107) A
compound having the formula (IX) described in (103) or a
pharmacologically acceptable salt thereof, wherein W is tetrazole.
(108) A compound having the formula (IX) described in (103) or a
pharmacologically acceptable salt thereof, wherein R.sup.1 is
hydrogen or a C.sub.1-8 alkyl group. (109) A compound having the
formula (IX) described in (103) or a pharmacologically acceptable
salt thereof, wherein R.sup.1 is hydrogen. (110) A compound having
the formula (IX) described in (103) or a pharmacologically
acceptable salt thereof, wherein R.sup.4 is hydrogen, and R.sup.5
is hydrogen or a C.sub.1-8 alkyl group. (111) A compound having the
formula (IX) described in (103) or a pharmacologically acceptable
salt thereof, wherein each of R.sup.4 and R.sup.5 is hydrogen.
(112) A compound having the formula (IX) described in (103) or a
pharmacologically acceptable salt thereof, wherein R.sup.2 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, carboxyl, a C.sub.2-8 acyl
group, or an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety. (113) A compound having the formula (IX) described in (103)
or a pharmacologically acceptable salt thereof, wherein R.sup.2 is
hydrogen. (114) A compound having the formula (IX) described in
(103) or a pharmacologically acceptable salt thereof, wherein
R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, carboxyl, a C.sub.2-8 acyl
group, or an alkoxycarbonyl group comprising a C.sub.1-8 alkoxy
moiety. (115) A compound having the formula (IX) described in (103)
or a pharmacologically acceptable salt thereof, wherein R.sup.3 is
hydrogen. (116)
5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]dia-
zepine-2,4(3H,5H)-dione sodium salt. (117) Paroxetine or a
pharmacologically acceptable salt thereof. (118) A diazepine
derivative having the following formula (X) or a pharmacologically
acceptable salt thereof:
##STR00054##
wherein each of R.sup.1 and R.sup.2 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0258] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0259] each of R.sup.4 and R.sup.5 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0260] R.sup.6 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0261] the ring shown below is a five-membered to eight-membered
non-aromatic ring optionally comprising one or two heteroatoms
selected from N, S, and O, and being condensed with the benzene
ring at 1- and 2-positions of the benzene ring;
##STR00055##
[0262] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, thiophene ring,
pyridine ring, pyrimidine ring, indole ring, indazole ring,
benzotriazole ring, benzisoxazole ring, benzimidazole ring, and
quinoline ring;
##STR00056##
[0263] Z is O or S;
[0264] when X is N, Y is C.dbd.O or C.dbd.S, and the double line
consisting of a solid line and a broken line is a single bond;
and
[0265] when X is C, Y is N, and the double line consisting of a
solid line and a broken line is a double bond.
(119) A diazepine derivative having the following formula (Xa) or a
pharmacologically acceptable salt thereof:
##STR00057##
wherein each of R.sup.11 and R.sup.12 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0266] R.sup.13 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0267] each of R.sup.14 and R.sup.15 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0268] R.sup.16 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0269] the ring shown below is a five-membered to eight-membered
non-aromatic ring optionally comprising one or two heteroatoms
selected from N, S, and O, and being condensed with the benzene
ring at 1- and 2-positions of the benzene ring;
##STR00058##
[0270] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, thiophene ring,
pyridine ring, pyrimidine ring, indole ring, indazole ring,
benzotriazole ring, benzisoxazole ring, benzimidazole ring, and
quinoline ring; and
##STR00059##
[0271] each of Z.sup.1 and Z.sup.2 independently is O or S.
(120) A diazepine derivative having the formula (Xa) described in
(119) or a pharmacologically acceptable salt thereof, wherein
R.sup.11 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
halogen atom, hydroxyl, amino, a C.sub.1-8 alkylamino group, a
C.sub.2-8 dialkylamino group, or a C.sub.2-8 acylamino group. (121)
A diazepine derivative having the formula (Xa) described in (119),
(120), or a pharmacologically acceptable salt thereof, wherein
R.sup.12 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, a C.sub.2-8 acylamino group, or a
C.sub.2-8 acylamino group having one to three halogen atoms. (122)
A diazepine derivative having the formula (Xa) described in one of
(119) to (121) or a pharmacologically acceptable salt thereof,
wherein R.sup.13 is hydrogen, a C.sub.1-8 alkyl group, or a
C.sub.1-8 alkyl group having one to three halogen atoms. (123) A
diazepine derivative having the formula (Xa) described in one of
(119) to (122) or a pharmacologically acceptable salt thereof,
wherein each of R.sup.14 and R.sup.15 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms. (124) A diazepine derivative having the
formula (Xa) described in one of (119) to (123) or a
pharmacologically acceptable salt thereof, wherein R.sup.16 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, or a heterocyclic
group optionally having one or more substituents. (125) A diazepine
derivative having the formula (Xa) described in one of (119) to
(123) or a pharmacologically acceptable salt thereof, wherein
R.sup.16 is tetrazolyl, triazolyl, pyridyl, pyrazolyl, oxadiazolyl,
isoxazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, oxazolyl, or
thiazolyl, each of which optionally has one or more substituents
selected from the group consisting of a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, and a C.sub.2-8 dialkylamino group. (126) A
diazepine derivative having the formula (Xa) described in one of
(119) to (123) or a pharmacologically acceptable salt thereof,
wherein R.sup.16 is tetrazolyl, triazolyl, pyridyl, imidazolyl,
oxazolyl, or thiazolyl, each of which optionally has one or more
substituents selected from the group consisting of a C.sub.1-8
alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, cyano, and
amino. (127) A diazepine derivative having the formula (Xa)
described in one of (119) to (126) or a pharmacologically
acceptable salt thereof, wherein the ring shown below is
tetrahydronaphthalene, indan, indoline, tetrahydroquinoline, or
tetrahydroisoquinoline.
##STR00060##
(128) A diazepine derivative having the formula (Xa) described in
one of (119) to (127) or a pharmacologically acceptable salt
thereof, wherein the ring shown below is benzene ring.
##STR00061##
(129) A diazepine derivative having the formula (Xa) described in
one of (119) to (128) or a pharmacologically acceptable salt
thereof, wherein each of Z.sup.1 and Z.sup.2 is O. (130) A
diazepine derivative having the following formula (Xb) or a
pharmacologically acceptable salt thereof:
##STR00062##
wherein each of R.sup.21 and R.sup.22 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, a C.sub.2-8
acylamino group, a C.sub.2-8 acylamino group having one to three
halogen atoms, a C.sub.1-8 alkylsulfonylamino group, carboxyl, a
C.sub.2-8 acyl group, an alkoxycarbonyl group comprising a
C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8 alkylthio group, a
C.sub.1-8 alkylsulfinyl group, a C.sub.1-8 alkylsulfonyl group, or
sulfamoyl;
[0272] R.sup.23 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0273] each of R.sup.24 and R.sup.25 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0274] R.sup.26 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents; and
[0275] p is 0 or 1.
(131) A diazepine derivative having the formula (Xb) described in
(130) or a pharmacologically acceptable salt thereof, wherein
R.sup.21 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
halogen atom, hydroxyl, amino, a C.sub.1-8 alkylamino group, a
C.sub.2-8 dialkylamino group, or a C.sub.2-8 acylamino group. (132)
A diazepine derivative having the formula (Xb) described in (130),
(131), or a pharmacologically acceptable salt thereof, wherein
R.sup.22 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, a C.sub.2-8 acylamino group, or a
C.sub.2-8 acylamino group having one to three halogen atoms. (133)
A diazepine derivative having the formula (Xb) described in one of
(130) to (132) or a pharmacologically acceptable salt thereof,
wherein R.sup.23 is hydrogen, a C.sub.1-8 alkyl group, or a
C.sub.1-8 alkyl group having one to three halogen atoms. (134) A
diazepine derivative having the formula (Xb) described in one of
(130) to (133) or a pharmacologically acceptable salt thereof,
wherein each of R.sup.24 and R.sup.25 independently is hydrogen, a
C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl group having one to
three halogen atoms. (135) A diazepine derivative having the
formula (Xb) described in one of (130) to (134) or a
pharmacologically acceptable salt thereof, wherein R.sup.26 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, a C.sub.2-8 dialkylamino group, or a heterocyclic
group optionally having one or more substituents. (136) A diazepine
derivative having the formula (Xb) described in one of (130) to
(134) or a pharmacologically acceptable salt thereof, wherein
R.sup.26 is tetrazolyl, triazolyl, pyridyl, pyrazolyl, oxadiazolyl,
isoxazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, oxazolyl, or
thiazolyl, each of which optionally has one or more substituents
selected from the group consisting of a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, and a C.sub.2-8 dialkylamino group. (137) A
diazepine derivative having the formula (Xb) described in one of
(130) to (133) or a pharmacologically acceptable salt thereof,
wherein R.sup.26 is tetrazolyl, triazolyl, pyridyl, imidazolyl,
oxazolyl, or thiazolyl, each of which optionally has one or more
substituents selected from the group consisting of a C.sub.1-8
alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, cyano, and
amino. (138) A diazepine derivative having the following formula
(XI) or a pharmacologically acceptable salt thereof:
##STR00063##
wherein R.sup.1 is hydrogen, a C-s alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one
to three halogen atoms, a C.sub.1-8 alkoxy group having one to
three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino,
a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino group, a
C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group having one
to three halogen atoms, a C.sub.1-8 alkylsulfonylamino group,
carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0276] R.sup.2 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or a C.sub.1-3 alkyl group having phenyl;
[0277] each of R.sup.3 and R.sup.4 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0278] R.sup.5 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino group
having one to five halogen atoms, a C.sub.2-8 dialkylamino group, a
C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group having one
to three halogen atoms, a C.sub.1-8 alkylsulfonylamino group,
carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0279] X is C or N;
[0280] the ring shown below is a heterocyclic ring selected from
the group consisting of thiophene ring, pyridine ring, pyrimidine
ring, quinoline ring, indole ring, indoline ring, benzimidazole
ring, indazole ring, benzisoxazole ring, and benzotriazole ring,
and the ring is combined with X at the carbon atom contained in the
heterocyclic ring as the member of the ring;
##STR00064##
[0281] Z is O or S;
[0282] when X is N, Y is C.dbd.O or C.dbd.S, and the double line
consisting of a solid line and a broken line is a single bond;
and
[0283] when X is C, Y is N, and the double line consisting of a
solid line and a broken line is a double bond.
(139) A diazepine derivative having the formula (XI) described in
(138) or a pharmacologically acceptable salt thereof, wherein
R.sup.1 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, a C.sub.2-8 acylamino group, or a
C.sub.2-8 acylamino group having one to three halogen atoms. (140)
A diazepine derivative having the formula (XI) described in (138),
(139), or a pharmacologically acceptable salt thereof, wherein
R.sup.2 is hydrogen, a C.sub.1-8 alkyl group, or a C.sub.1-8 alkyl
group having one to three halogen atoms. (141) A diazepine
derivative having the formula (XI) described in one of (138) to
(140) or a pharmacologically acceptable salt thereof, wherein each
of R.sup.3 and R.sup.4 independently is hydrogen, a C.sub.1-8 alkyl
group, or a C.sub.1-8 alkyl group having one to three halogen
atoms. (142) A diazepine derivative having the formula (XI)
described in one of (138) to (141) or a pharmacologically
acceptable salt thereof, wherein R.sup.5 is hydrogen, a C.sub.1-8
alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, or a heterocyclic group optionally
having one or more substituents. (143) A diazepine derivative
having the formula (XI) described in one of (138) to (141) or a
pharmacologically acceptable salt thereof, wherein R.sup.5 is
tetrazolyl, triazolyl, imidazolyl, oxazolyl, or thiazolyl, each of
which optionally has one or more substituents selected from the
group consisting of a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
and a C.sub.2-8 dialkylamino group. (144) A diazepine derivative
having the formula (XI) described in one of (138) to (141) or a
pharmacologically acceptable salt thereof, wherein R.sup.5 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, or
hydroxyl. (145) A diazepine derivative having the formula (XI)
described in one of (138) to (144) or a pharmacologically
acceptable salt thereof, wherein Z is O. (146) A diazepine
derivative having the following formula (XIa) or a
pharmacologically acceptable salt thereof:
##STR00065##
wherein R.sup.11 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0284] each of R.sup.13 and R.sup.14 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino, or a
C.sub.1-3 alkyl group having phenyl;
[0285] R.sup.15 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino group
having one to five halogen atoms, a C.sub.2-8 dialkylamino group, a
C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group having one
to three halogen atoms, a C.sub.1-8 alkylsulfonylamino group,
carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents; and
[0286] the ring shown below is a heterocyclic ring selected from
the group consisting of thiophene ring, pyridine ring, pyrimidine
ring, quinoline ring, indole ring, indoline ring, benzimidazole
ring, indazole ring, benzisoxazole ring, and benzotriazole ring,
and the ring is combined with X at the carbon atom contained in the
heterocyclic ring as the member of the ring.
##STR00066##
(147) A diazepine derivative having the formula (XIa) described in
(146) or a pharmacologically acceptable salt thereof, wherein
R.sup.11 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.2-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
a C.sub.2-8 dialkylamino group, a C.sub.2-8 acylamino group, or a
C.sub.2-8 acylamino group having one to three halogen atoms. (148)
A diazepine derivative having the formula (XIa) described in (146)
or a pharmacologically acceptable salt thereof, wherein R.sup.11 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, or a
halogen atom. (149) A diazepine derivative having the formula (XIa)
described in one of (146) to (148) or a pharmacologically
acceptable salt thereof, wherein each of R.sup.13 and R.sup.14
independently is hydrogen, a C.sub.1-8 alkyl group, or a C.sub.1-8
alkyl group having one to three halogen atoms. (150) A diazepine
derivative having the formula (XIa) described in one of (146) to
(149) or a pharmacologically acceptable salt thereof, wherein
R.sup.15 is hydrogen, C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl
group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one
to three halogen atoms, a C.sub.1-8 alkoxy group having one to
three halogen atoms, a halogen atom, hydroxyl, nitro, cyano, amino,
a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino group, or a
heterocyclic group optionally having one or more substituents.
(151) A diazepine derivative having the formula (XIa) described in
one of (146) to (149) or a pharmacologically acceptable salt
thereof, wherein R.sup.15 is tetrazolyl, triazolyl, imidazolyl,
oxazolyl, or thiazolyl, each of which optionally has one or more
substituents selected from the group consisting of a C.sub.1-8
alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, and a C.sub.2-8 dialkylamino
group. (152) A diazepine derivative having the formula (XIa)
described in one of (146) to (149) or a pharmacologically
acceptable salt thereof, wherein R.sup.15 is hydrogen, a C.sub.1-8
alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms or hydroxyl. (153) A compound having the
following formula (XII) or a pharmacologically acceptable salt
thereof:
##STR00067##
wherein each of R.sup.1 and R.sup.2 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0287] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0288] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, an aralkyl group comprising a
C.sub.6-10 aryl moiety and a C.sub.1-3 alkylene moiety, a C.sub.1-8
alkyl group having hydroxyl, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino
group having one to five halogen atoms, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, benzenesulfonylamino optionally having one or more
substituents, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl
group comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0289] the ring shown below is a five-membered to eight-membered
ring optionally comprising one or more heteroatoms selected from N,
S, and O as the members of the ring, and being condensed with the
benzene ring at 1- and 2-positions of the benzene ring; and
##STR00068##
[0290] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, pyridine ring,
pyrimidine ring, quinoline ring, indole ring, indoline ring,
benzimidazole ring, indazole ring, benzisoxazole ring, and
benzotriazole ring.
##STR00069##
(154) A compound having the formula (XII) described in (153) or a
pharmacologically acceptable salt thereof, wherein each of R.sup.1
and R.sup.2 independently is hydrogen, a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, or amino. (155) A
compound having the formula (XII) described in (153), (154), or a
pharmacologically acceptable salt thereof, wherein R.sup.3 is
hydrogen or a C.sub.1-8 alkyl group. (156) A compound having the
formula (XII) described in one of (153) to (155) or a
pharmacologically acceptable salt thereof, wherein R.sup.4 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a
C.sub.1-8 alkyl group having hydroxyl, a halogen atom, hydroxyl,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.2-8
dialkylamino group, a C.sub.1-8 alkylsulfonylamino group,
benzenesulfonylamino optionally having one or more substituents,
phenyl optionally having one or more substituents, or a
heterocyclic group optionally having one or more substituents.
(157) A compound having the formula (XII) described in one of (153)
to (155) or a pharmacologically acceptable salt thereof, wherein
R.sup.4 is tetrazolyl, triazolyl, pyridyl, imidazolyl, oxazolyl, or
thiazolyl, each of which optionally has one or more substituents
selected from the group consisting of a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8
alkylamino group, and a C.sub.2-8 dialkylamino group. (158) A
compound having the formula (XII) described in one of (153) to
(155) or a pharmacologically acceptable salt thereof, wherein
R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, cyano, amino, a C.sub.1-8 alkylamino group, a
C.sub.2-8 dialkylamino group, or benzenesulfonylamino optionally
having one or more substituents selected from the group consisting
of a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a halogen
atom, and nitro. (159) A compound having the formula (XII)
described in one of (153) to (158) or a pharmacologically
acceptable salt thereof, wherein the ring shown below is
naphthalene ring, tetrahydronaphthalene ring, or indan ring.
##STR00070##
(160) A compound having the formula (XII) described in one of (153)
to (159) or a pharmacologically acceptable salt thereof, wherein
the ring shown below is benzene ring or indole ring.
##STR00071##
(161) A compound having the following formula (XIIa) or a
pharmacologically acceptable salt thereof:
##STR00072##
wherein each of R.sup.11 and R.sup.12 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0291] R.sup.13 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0292] R.sup.14 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, an aralkyl group comprising a
C.sub.6-10 aryl moiety and a C.sub.1-3 alkylene moiety, a C.sub.1-8
alkyl group having hydroxyl, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino
group having one to five halogen atoms, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, benzenesulfonylamino optionally having one or more
substituents, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl
group comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents; and
[0293] the ring shown below is naphthalene ring,
tetrahydronaphthalene ring, or indan ring.
##STR00073##
(162) A compound having the formula (XIIa) described in (161) or a
pharmacologically acceptable salt thereof, wherein each of R.sup.11
and R.sup.12 independently is hydrogen, a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, or amino. (163) A
compound having the formula (XIIa) described in (161), (162) or a
pharmacologically acceptable salt thereof, wherein R.sup.13 is
hydrogen or a C.sub.1-8 alkyl group. (164) A compound having the
formula (XIIa) described in one of (161) to (163) or a
pharmacologically acceptable salt thereof, wherein R.sup.14 is
hydrogen, a C.sub.1-8 alkyl group, a C-s alkoxy group, a C.sub.1-8
alkyl group having one to three halogen atoms, a C.sub.1-8 alkoxy
group having one to three halogen atoms, a C.sub.1-8 alkyl group
having hydroxyl, a halogen atom, hydroxyl, cyano, amino, a
C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino group, a
C.sub.1-8 alkylsulfonylamino group, benzenesulfonylamino optionally
having one or more substituents, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents. (165) A compound having the formula (XIIa)
described in one of (161) to (163) or a pharmacologically
acceptable salt thereof, wherein R.sup.14 is tetrazolyl, triazolyl,
pyridyl, imidazolyl, oxazolyl, or thiazolyl, each of which
optionally has one or more substituents selected from the group
consisting of a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, nitro, cyano, amino, a C.sub.1-8 alkylamino group,
and a C.sub.2-8 dialkylamino group. (166) A compound having the
formula (XIIa) described in one of (161) to (163) or a
pharmacologically acceptable salt thereof, wherein R.sup.14 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a halogen
atom, hydroxyl, cyano, amino, a C.sub.1-8 alkylamino group, a
C.sub.2-8 dialkylamino group, or benzenesulfonylamino optionally
having one or more substituents selected from the group consisting
of a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a halogen
atom, and nitro. (167) A compound having the formula (XIIa)
described in one of (161) to (166) or a pharmacologically
acceptable salt thereof, wherein the ring shown below is
naphthalene ring.
##STR00074##
(168) A compound having the formula (XIIa) described in (161) or a
pharmacologically acceptable salt thereof, wherein R.sup.11,
R.sup.12, R.sup.13, and the ring shown below are the same as those
defined in (161), and R.sup.14 is NHSO.sub.2R, wherein R is an aryl
group optionally having one or more substituents or a heterocyclic
group optionally having one or more substituents.
##STR00075##
(169) A compound having the formula (XIIa) described in (168) or a
pharmacologically acceptable salt thereof, wherein R is phenyl,
naphthyl, quinolyl, pyridyl, or thienyl, which of which optionally
has one or more substituents, a C.sub.1-8 alkyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
hydroxyl, amino, nitro, or a halogen atom. (170) A compound having
the following formula (XIII) or a pharmacologically acceptable salt
thereof:
##STR00076##
wherein each of R.sup.1 and R.sup.2 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0294] R.sup.3 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0295] R.sup.4 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, an aralkyl group comprising a
C.sub.6-10 aryl moiety and a C.sub.1-3 alkylene moiety, a C.sub.1-8
alkyl group having hydroxyl, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5 alkylamino
group having one to five halogen atoms, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, benzenesulfonylamino optionally having one or more
substituents, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl
group comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, sulfamoyl, phenyl optionally having one or
more substituents, or a heterocyclic group optionally having one or
more substituents;
[0296] the ring shown below is a five-membered to eight-membered
ring optionally comprising one or two nitrogen atoms as the members
of the ring, and being condensed with the benzene ring at 1- and
2-positions of the benzene ring; and
##STR00077##
[0297] the ring shown below is an aromatic ring selected from the
group consisting of benzene ring, naphthalene ring, pyridine ring,
pyrimidine ring, quinoline ring, indole ring, indoline ring,
benzimidazole ring, pyrazole ring, indazole ring, benzisoxazole
ring, and benzotriazole ring;
##STR00078##
[0298] provided that R.sup.4 is not hydrogen, a C.sub.1-8 alkyl
group, or a halogen atom in the case that the ring shown below is
benzene ring.
##STR00079##
(171) A compound having the formula (XIII) described in (170) or a
pharmacologically acceptable salt thereof, wherein each of R.sup.1
and R.sup.2 independently is hydrogen, a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, or amino. (172) A
compound having the formula (XIII) described in (170), (171), or a
pharmacologically acceptable salt thereof, wherein R.sup.3 is
hydrogen or a C.sub.1-8 alkyl group. (173) A compound having the
formula (XIII) described in one of (170) to (172) or a
pharmacologically acceptable salt thereof, wherein R.sup.4 is
hydrogen, a C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a
C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, a
C.sub.1-8 alkyl group having hydroxyl, a halogen atom, hydroxyl,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.2-8
dialkylamino group, a C.sub.1-8 alkylsulfonylamino group,
benzenesulfonylamino optionally having one or more substituents,
phenyl optionally having one or more substituents, or a
heterocyclic group optionally having one or more substituents.
(174) A compound having the formula (XIII) described in one of
(170) to (172) or a pharmacologically acceptable salt thereof,
wherein R.sup.4 is tetrazolyl, triazolyl, pyridyl, imidazolyl,
oxazolyl, or thiazolyl, each of which optionally has one or more
substituents selected from the group consisting of a C.sub.1-8
alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group
having one to three halogen atoms, a C.sub.1-8 alkoxy group having
one to three halogen atoms, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, and a C.sub.2-8 dialkylamino
group. (175) A compound having the formula (XIII) described in one
of (170) to (172) or a pharmacologically acceptable salt thereof,
wherein R.sup.4 is a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl
group having one to three halogen atoms, a C.sub.1-8 alkoxy group
having one to three halogen atoms, hydroxyl, cyano, amino, a
C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino group, or
benzenesulfonylamino optionally having one or more substituents
selected from the group consisting of a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a halogen atom, and nitro. (176) A compound
having the formula (XIII) described in one of (170) to (175) or a
pharmacologically acceptable salt thereof, wherein the ring shown
below is naphthalene ring, tetrahydronaphthalene ring, or indan
ring.
##STR00080##
(177) A compound having the formula (XIII) described in one of
(170) to (176) or a pharmacologically acceptable salt thereof,
wherein the ring shown below is benzene ring or indole ring.
##STR00081##
(178) A compound having the following formula (XIIIa) or a
pharmacologically acceptable salt thereof:
##STR00082##
wherein each of R.sup.11 and R.sup.12 independently is hydrogen, a
C.sub.1-8 alkyl group, a C.sub.2-8 alkenyl group, a C.sub.1-8
alkoxy group, a C.sub.1-8 alkyl group having one to three halogen
atoms, a C.sub.1-8 alkoxy group having one to three halogen atoms,
an aralkyl group comprising a C.sub.6-10 aryl moiety and a
C.sub.1-3 alkylene moiety, a halogen atom, hydroxyl, nitro, cyano,
amino, a C.sub.1-8 alkylamino group, a C.sub.2-8 dialkylamino
group, a C.sub.2-8 acylamino group, a C.sub.2-8 acylamino group
having one to three halogen atoms, a C.sub.1-8 alkylsulfonylamino
group, carboxyl, a C.sub.2-8 acyl group, an alkoxycarbonyl group
comprising a C.sub.1-8 alkoxy moiety, carbamoyl, a C.sub.1-8
alkylthio group, a C.sub.1-8 alkylsulfinyl group, a C.sub.1-8
alkylsulfonyl group, or sulfamoyl;
[0299] R.sup.13 is hydrogen, a C.sub.1-8 alkyl group, a C.sub.2-8
alkenyl group, a C.sub.1-8 alkyl group having one to three halogen
atoms, or an aralkyl group comprising a C.sub.6-10 aryl moiety and
a C.sub.1-3 alkylene moiety;
[0300] R.sup.14 is a C.sub.2-8 alkenyl group, a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, an
aralkyl group comprising a C.sub.6-10 aryl moiety and a C.sub.1-3
alkylene moiety, a C.sub.1-8 alkyl group having hydroxyl, hydroxyl,
nitro, cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.1-5
alkylamino group having one to five halogen atoms, a C.sub.2-8
dialkylamino group, a C.sub.2-8 acylamino group, a C.sub.2-8
acylamino group having one to three halogen atoms, a C.sub.1-8
alkylsulfonylamino group, benzenesulfonylamino optionally having
one or more substituents, carboxyl, a C.sub.2-8 acyl group, an
alkoxycarbonyl group comprising a C.sub.1-8 alkoxy moiety,
carbamoyl, a C.sub.1-8 alkylthio group, a C.sub.1-8 alkylsulfinyl
group, a C.sub.1-8 alkylsulfonyl group, sulfamoyl, phenyl
optionally having one or more substituents, or a heterocyclic group
optionally having one or more substituents; and
[0301] the ring shown below is naphthalene ring,
tetrahydronaphthalene ring, or indan ring.
##STR00083##
(179) A compound having the formula (XIIIa) described in (178) or a
pharmacologically acceptable salt thereof, wherein each of R.sup.11
and R.sup.12 independently is hydrogen, a C.sub.1-8 alkyl group, a
C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl group having one to three
halogen atoms, a C.sub.1-8 alkoxy group having one to three halogen
atoms, a halogen atom, hydroxyl, nitro, cyano, or amino. (180) A
compound having the formula (XIIIa) described in (178), (179), or a
pharmacologically acceptable salt thereof, wherein R.sup.13 is
hydrogen. (181) A compound having the formula (XIIIa) described in
one of (178) to (180) or a pharmacologically acceptable salt
thereof, wherein R.sup.14 is a C.sub.1-8 alkoxy group, a C.sub.1-8
alkyl group having one to three halogen atoms, a C.sub.1-8 alkoxy
group having one to three halogen atoms, a C.sub.1-8 alkyl group
having hydroxyl, hydroxyl, cyano, amino, a C.sub.1-8 alkylamino
group, a C.sub.2-8 dialkylamino group, a C.sub.1-8
alkylsulfonylamino group, benzenesulfonylamino optionally having
one or more substituents, phenyl optionally having one or more
substituents, or a heterocyclic group optionally having one or more
substituents. (182) A compound having the formula (XIIIa) described
in one of (178) to (180) or a pharmacologically acceptable salt
thereof, wherein R.sup.14 is tetrazolyl, triazolyl, pyridyl,
imidazolyl, oxazolyl, or thiazolyl, each of which optionally has
one or more substituents selected from the group consisting of a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a C.sub.1-8 alkyl
group having one to three halogen atoms, a C.sub.1-8 alkoxy group
having one to three halogen atoms, a halogen atom, hydroxyl, nitro,
cyano, amino, a C.sub.1-8 alkylamino group, and a C.sub.2-8
dialkylamino group. (183) A compound having the formula (XIIIa)
described in one of (178) to (180) or a pharmacologically
acceptable salt thereof, wherein R.sup.14 is a C.sub.1-8 alkoxy
group, a C.sub.1-8 alkyl group having one to three halogen atoms, a
C.sub.1-8 alkoxy group having one to three halogen atoms, hydroxyl,
cyano, amino, a C.sub.1-8 alkylamino group, a C.sub.2-8
dialkylamino group, or benzenesulfonylamino optionally having one
or more substituents selected from the group consisting of a
C.sub.1-8 alkyl group, a C.sub.1-8 alkoxy group, a halogen atom,
and nitro. (184) A compound having the formula (XIIIa) described in
one of (178) to (183) or a pharmacologically acceptable salt
thereof, wherein the ring shown below is naphthalene ring.
##STR00084##
(185)
5-[3-(1H-tetrazole-5-yl)phenyl]-8,9,10,11-tetrahydronaphtho[2,1-b][-
1,4]diazepine-2,4(3H,5H)-dione sodium salt, [0302]
5-(1H-indol-6-yl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione,
[0303]
4-[3-(1H-tetrazole-5-yl)phenyl]-1,4-dihydrobenzo[f]quinoxaline-2,3-
-dione sodium salt, or [0304]
4-[3-(1H-tetrazole-5-yl)phenyl]-1H-benzo[h]quinazolin-2-one sodium
salt.
[0305] The above-mentioned compounds can be prepared according to
known processes. For example, the compounds described in (2) to (4)
can be prepared according to a process described in WO 2004/085440.
The compounds described in (5) and (117) can be prepared according
to a process described in Japanese Patent Publication No.
59(1984)-48826. The compounds described in (8) to (16) can be
prepared according to a process described in WO 2007/072974. The
compounds described in (17) to (36) can be prepared according to a
process described in WO 2007/074970. The compounds described in
(37) to (52) can be prepared according to a process described in WO
2008/023847. The compounds described in (53) to (79) can be
prepared according to a process described in WO 2009/022730. The
compounds described in (80) to (94) can be prepared according to a
process described in WO 2009/022731. The compounds described in
(95) to (102) can be prepared according to a process described in
WO 2010/090300. The compounds described in (103) to (116) can be
prepared according to a process described in WO 2010/093061.
[0306] The compounds described in (7) and (117) such as paroxetine,
imipramine are known compounds. The chemical structures and the
documents disclosing the processes for preparation of the compounds
are described in The MERCK INDEX FOURTEENTH RDITION (2006) or the
like. Further, these compounds are commercially available.
[0307] The selective serotonin reuptake inhibitors described in (6)
include paroxetine, fluoxetine, fluvoxamine, and citalopram.
[0308] The above-mentioned WO 2004/085440, WO 2007/072974, WO
2007/074970, WO 2008/023847, WO 2009/022730, WO 2009/022731, WO
2010/090300, WO 2010/093061, WO 2007/049825, and WO 2008/020651
describe that the compounds described in (2) to (117) have
P2X.sub.4 receptor antagonism.
[0309] The compounds described in (118) to (185) also have P2X4
receptor antagonism, and can be prepared according to the processes
described in the documents cited in the processes for preparation
of the compounds described in (2) to (5) and (8) to (116).
[0310] The pharmacologically acceptable salts in the active
ingredients of the present invention include a salt with an acid
(e.g., as hydrochloric acid, acetic acid, benzoic acid, fumaric
acid, besylic acid), an alkali metal (e.g., sodium, potassium,
lithium), or an amine.
[0311] The active ingredients of the present invention can be a
geometrical (cis-trans) isomer or an optical isomer such as an
optically active substance and racemic modification, each of which
is included within the scope of the invention. Hydrates can also be
used as the active ingredients of the present invention.
[0312] The results of the pharmacological experiments are described
below.
[0313] The effect of P2X.sub.4 receptor antagonist on herpes
zoster-associated pain in acute phase was examined using a mouse
model (Examples 3 and 4).
[0314] The results of Examples 3 and 4 as well as FIGS. 4 and 5
show analgesic activities of paroxetine and the compound A
(5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]di-
azepine-2,4(3H,5H)-dione sodium salt), which have P2X.sub.4
receptor antagonism, on an acute phase of herpes zoster-induced
pain. The results suggest that P2X.sub.4 receptor plays a major
role in the acute phase of herpes zoster-induced pain.
[0315] Further, immunohistological analysis and real time RT-PCR
analysis using the mouse model of herpes zoster show that spinal
microglial cells proliferate in the acute phase of herpes zoster,
and that expression of P2X.sub.4 receptor is increased in activated
microglia. The results suggest that, in acute phase of the herpes
zoster, spinal microglia become activated with proliferation and
increase expression of P2X.sub.4 receptors (Example 2, FIGS. 1-3)
Accordingly, proliferation and activation of microglia and
P2X.sub.4 receptor with development of the syndrome of the herpes
zoster in acute phase play important roles in causing the acute
phase pain by herpes zoster. Therefore, it is suggested that
P2X.sub.4 receptor antagonist can be an effective therapeutic agent
for acute phase pain of herpes zoster.
[0316] Aciclovir, Valaciclovir, and Famciclovir are conventional
anti-herpetic drugs and have been used for treating herpes zoster
in acute phase. It has been reported that they have an effect of
accelerating healing exanthema and may shorten the duration of the
zoster-associated pain (Wood M J, et al., Clin Infect Dis, 1996,
22:341-347; Beutner K R, et al., Antimicrob Agents Chemother, 1995,
39:1546-1553; Tyring S K., Semin Dermatol, 1996, 15:27-31; Wood M
J, et al., N Engl J Med, 1994, 330:896-900; Rowbotham M C., Semin
Nuerol, 1994, 14:247-254; Wood M J, et al., Am J Med, 1988,
85:79-83; Huff J C, et al., Am J Med, 1988, 85:84-89; and
McKendrick M W, et al., BMJ, 1989, 298:431). It has also been
suggested that continuous desensitization is necessary for
preventing acute phase pain of herpes zoster from changing into
postherpetic neuralgia (Manabe et al., Clin J Pain, 1995,
11:220-228). Therefore, it is suggested that combinations of the
above-mentioned drugs with the P2X.sub.4 receptor antagonist may
show a stronger analgesic activity by removing acute phase pain to
prevent or treat the postherpetic neuralgia.
[0317] The preventive or therapeutic agent of the present invention
can be administered to human beings by ordinary administration
methods such as oral administration or parenteral
administration.
[0318] The compound can be granulated in ordinary manners for the
preparation of pharmaceuticals. For instance, the compound can be
processed to give tablets, granule, powder, capsule, suspension,
injection, suppository, and the like.
[0319] Ordinary additives such as vehicles, disintegrators,
binders, lubricants, dyes, and diluents are used for the
preparation of these pharmaceuticals such as tablets. As the
vehicles, lactose, D-mannitol, crystalline cellulose, and glucose
can be mentioned. Further, there can be mentioned starch and
carboxymethylcellulose calcium (CMC-Ca) as the disintegrators,
magnesium stearate and talc as the lubricants, and
hydroxylpropylcellulose (HPC), gelatin and polyvinylpyrrolidone
(PVP) as the binders. The preparation of an injection can be made
using solvents, stabilizers, dissolution-aids, suspensions,
emulsifiers, soothing agents, buffers, or preservatives.
[0320] The compound of the invention can be administered to an
adult generally in an amount of approximately 0.01 mg to 100 mg a
day by parenteral administration and 1 mg to 2,000 mg a day by oral
administration. The dosage can be adjusted in consideration of age
and conditions of the patient.
EXAMPLES
Example 1
Experimental Procedure
[0321] P2X.sub.4 receptor antagonisms of the compound A
(5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]di-
azepine-2,4(3H,5H)-dione sodium salt; described in Example 14 of WO
2010/093061) and paroxetine were measured as described below.
[0322] ATP receptors (human P2X.sub.4) were introduced into 1321N1
cells, and used as a stable ATP receptorexpressing system. The
obtained P2X.sub.4 expressing 1321N1 cells were plated in a 96-well
assay plate, and cultured 24 hours at 37.degree. C. in an
atmosphere of 5% CO.sub.2 for calcium assay. Fura-2 AM calcium
fluorescent indicator was dissolved in an extracellular solution
for calcium imaging. The obtained solution was loaded onto the
plated cells, and placed at room temperature for 45 minutes to
introduce Fura-2 AM into the cells. The fluorescence was detected
by FLUOstar OPTIMA micro plate reader (BMG Labtech). The cells were
alternatively illuminated with two excitations wavelengths (340 nm
and 380 nm) via xenon lamp, and the emitted fluorescence was
measured at 510 nm. The fluorescence changes after the treatment of
1 .mu.M ATP were monitored and determined the fluorescence ratio
(F340/F380) as the index of intracellular calcium change. Tested
compounds were treated to cells 15 min before the addition of ATP,
and the inhibitory activities of compounds were calculated by
comparing the Ca2+ response with control in the absence of tested
compound.
Experimental Results
TABLE-US-00001 [0323] TABLE 1 Test compound IC.sub.50 (.mu.M)
Paroxetine 4.6 Compound A 0.27
Example 2
[0324] Immunohistological and RT-real time PCR analyses were
conducted using the mouse model of herpes zoster to study that
spinal microglia cells proliferate in acute phase of herpes zoster,
and expression of P2X.sub.4 receptor increases in activated
microglia.
Experimental Procedure
[0325] Epidermis of the right hind leg (lower part of knee joint)
of shaven female C57BL/6J mice was chopped with a bundle of ten 26
G injection needles, and coated with a solution (1.times.10.sup.6
pfu/site) of herpes simplex virus Type I (HSV-1), which as well as
varicella zoster virus, belongs to Herpesviridae (family) (Takasaki
I, et al., Anesthesiology, 2002, 96:1168-1174). Seven days after
infection, the spinal cord was collected after perfusion of 4%
neutral buffered paraformaldehyde, replaced with 30% sucrose
solution, embedded with OCT compound to prepare frozen slices. A
specimen in cross section was prepared at the fifth lumbar level of
the spinal cord, and was subjected to a fluorescent double
immunostaining according to Alexa Fluor 488, 546 using OX42
antibody, which has widely been used as a microglia marker, and
P2X.sub.4 receptor antibody.
Experimental Results
[0326] The obtained fluorescent immunostaining images are shown in
FIG. 1. Seven days after infection, immunofluorescence intensities
of OX42 (microglia marker) and P2X.sub.4 receptor increase on the
side treated with HSV-1 (right figures) within L5 segment of the
spinal cord, compared with the side with no HSV-1 treatment (left
figures). Further, it is observed that the two signals are
co-localized clearly (the area indicated by the arrow in the upper
right figure and the area circled with the dotted line in the lower
right figure).
[0327] The results of RT-real time PCR analysis of the herpes
zoster manifestation are shown in FIG. 2. Mice were infected with
HSV-1 to cause manifestation of herpes zoster. The total RNA was
extracted from the L5 segment of the spinal cord from third day to
twentieth day in the acute phase, and subjected to a reverse
transcription to obtain cDNA. The changes in mRNA expression of
Iba1, which is a calcium-binding protein with microglia-specific
expression, and P2X.sub.4 receptor was studied using a Taq Man real
time PCR method. The Iba1 mRNA expression was significantly
increased from five days to twenty days after infection, and the
increase peaked at day seven (FIG. 2). With respect to P2X.sub.4
receptor, a peak was also observed seven days after infection, and
significant increase was observed from five days to fifteen days
after infection (FIG. 3). As is evident from the results, the
time-course of the increase in mRNA expressions of Iba1 (microglia
marker) and P2X.sub.4 receptor was almost same. Taken these results
together, it is suggested that the expression of P2X.sub.4
receptors in the spinal cord is increased in the proliferated
microglia that occurs in the acute phase of herpes zoster.
Example 3
Experimental Procedure
[0328] The effect of P2X.sub.4 receptor antagonist in
zoster-associated pain in acute phase was studied using the mouse
model of herpes zoster described in Example 2. At seven days after
infection corresponding to the time of zoster-associated pain in
acute phase and thirty days after infection corresponding to the
time of postherpetic neuralgia, paroxetine (30 mg/kg, 50 mg/kg) or
the solvent (tap water) was orally administered. It has been
reported that paroxetine functions as an inhibitor of P2X.sub.4
receptor (Nagata K, Imai T et al., Molecular Pain, 2009, 5:20). The
pain-associated reaction of the hindpaw on the HSV-1 infection side
was measured and evaluated referring to the response to a contact
stimulant using a paint-brush. The mouse was placed into a cage for
measurement, and accustomed to the environment for 1 hour or more.
The plantar surface of the right hindpaw was vertically stroked
with the paintbrush along the direction from toe to heal, and this
was repeated six times at intervals of several seconds. The pain
reaction was evaluated as follows:
Score 0: No reaction Score 1: Lifting of hind leg Score 2: Sharp
evasion reaction and flinching of hind leg
[0329] Each individual pain score was calculated by averaging six
scores.
Experimental Results
[0330] FIG. 4 shows influence of oral administration of paroxetine
on acute phase pain of herpes zoster. Mice were inoculated with
HSV-1, and the pain score reached the almost maximum seven days
after infection. Seven days after infection, threshold of the pain
was significantly improved from 1 hour to 4 hours after
administration of paroxetine (30 mg/kg) into the mice. In the group
of administration of 50 mg/kg of paroxetine, it was observed that
threshold of the pain was continuously improved from 30 minutes to
8 hours after administration (the right figure of FIG. 4). Thirty
days after infection, 30 mg/kg of paroxetine did not show any
significant improvement on the threshold of the pain, and only in
the group of 50 mg/kg of paroxetine, significant improvement was
observed on the threshold of the pain 30 minutes, 1 hour, and 4
hours after administration (the left figure of FIG. 4).
Example 4
Experimental Procedure
[0331] The effect of P2X.sub.4 receptor antagonism on
zoster-associated pain in acute phase was studied using the mouse
model of herpes zoster described in Example 2. From five days to
seven days after infection corresponding to the time of
zoster-associated pain in acute phase, the compound A (10
pmol/mouse, 30 pmol/mouse), which is a P2X.sub.4 receptor-specific
antagonist, or PBS was intrathecally administered twice a day, at
AM 10:00 to 11:00 and PM 6:00 to 7:00. Threshold of the pain was
measured before administration of the drug (AM 9:30 to 10:00 and PM
5:30 to 6:00). Pain-associated reaction on the HSV-1 infection side
hindpaw was measured using von Frey Filament (0.16 g). The mouse
was placed into a cage for measurement, and accustomed to the
environment for 1 hour or more. The von Frey filament was
vertically applied to the right hindpaw for three to five seconds
to bend the filament slightly, and this was repeated six times at
intervals of several seconds. The pain reaction was evaluated as
follows:
Score 0: No reaction Score 1: Lifting of hind leg Score 2: Sharp
evasion reaction and flinching of hind leg
[0332] Each individual pain score was calculated by averaging six
scores. The allodynia score (%) was calculated as the average score
of each group by counting the maximum reaction score 2 as 100%.
Experimental Results
[0333] FIG. 5 shows the influence of intrathecal administration of
the compound A on acute phase pain of herpes zoster.
[0334] The arrow in the graph indicates the time of the intrathecal
administration of the compound A (10 pmol/mouse, 30 pmol/mouse) or
PBS twice a day at AM 10:00 to 11:00 and at PM 6:00 to 7:00 after
five days to seven days after infection. Threshold of the pain was
measured before administration of the drugs (AM 9:30 to 10:00 and
PM 5:30 to 6:00).
[0335] In the group of mice inoculated with HSV-1 and administered
with PBS, the pain score reached the almost maximum seven days
after infection. In the groups administered with 10 pmol/mouse and
30 pmol/mouse of the compound A, it was observed that the threshold
score of the pain was significantly suppressed compared with the
pain threshold score after the first administration.
* * * * *